Further reading

Dyson JK, Anstee QM, McPherson S. Non-alcoholic fatty liver disease: a practical approach to treatment. Frontline Gastroenterol 2014; 5:277–286.

Gawrieh S, Chalasani N. NAFLD fibrosis score: is it ready for wider use in clinical practice and for clinical trials? Gastroenterology 2013; 145:717–719.

Newsome PN, Allison ME, Andrews PA et al. Guidelines for liver transplantation for patients with non-alcoholic steatohepatitis. Gut 2012; 61:484–500.

Cirrhosis

In cirrhosis, the liver architecture is diffusely abnormal and interferes with liver blood flow and function; this leads to the clinical manifestations of portal hypertension and liver failure.

image Pathogenesis

Although the liver has a remarkable capacity to adapt to injury through tissue repair, chronic injury results in inflammation, matrix deposition, necrosis and angiogenesis, all of which lead to fibrosis (Fig. 14.21). Liver injury causes necrosis and apoptosis, releasing cell contents and reactive oxygen species (ROS). This activates hepatic stellate cells and tissue macrophages through the CC-chemokine ligand 2–CC-chemokine receptor 2 (CCL2–CCR2) axis (see p. 440). These cells phagocytose necrotic and apoptotic cells and secrete pro-inflammatory mediators, including transforming growth factor-beta (TGF-β); this leads to transdifferentiation of stellate cells to myofibro­blasts and platelet-derived growth factor (PDGF), which stimulates myofibroblast proliferation. Macrophages degrade scar matrix by secretion of matrix metalloproteinases (MMPs), but this is inhibited by concurrent myofibroblast and macrophage production of tissue inhibitors of metalloproteinases (TIMPs). This results in progressive matrix deposition and scar accumulation. Increased gut permeability and hepatic lipopolysaccharide–Toll-like receptor 4 (LPS–TLR4) signalling also promotes fibrogenesis. Repetitive or chronic injury and inflammation perpetuate this process.

image
Figure 14.21 Pathogenesis of fibrosis. The normal liver is shown on the left. Activation of the stellate cell is followed by proliferation of fibroblasts and the deposition of collagen.

If the cause of fibrosis is eliminated (e.g. treatment of viral hepatitis), resolution (complete reversal to near-normal liver architecture) of early fibrosis can occur. In cirrhosis, regression (improvement, not reversal) occurs, which improves clinical outcomes. Antifibrotic therapies are emerging (including stem cell transplant strategies) but currently liver transplantation is the only available treatment for liver failure.

image Investigations

Investigations aim to assess the severity and type of liver disease.

image Management

Management is that of the complications of decompensated cirrhosis. Patients should undergo 6-monthly ultrasound to screen for the early development of HCC (see p. 485), as all therapeutic strat­egies work best with small, single tumours.

Treatment of the underlying cause may arrest or reverse cirrhosis. Patients with compensated cirrhosis should lead a normal life. Those at risk should receive hepatitis A and B vaccination. The only dietary restriction is to reduce salt intake (≤2 g sodium per day). Alcohol should be avoided, as should aspirin and non-steroidal anti-inflammatory drugs (NSAIDs), which may precipitate gastro­intestinal bleeding or renal impairment.

image Prognosis

Prognosis is extremely variable. In general, the 5-year survival rate is approximately 50%, depending on the stage at which diagnosis is made. Poor prognostic indicators are shown in Box 14.13. Development of any complication usually worsens the prognosis.

There are a number of prognostic classifications based on modifications of Child's grading (A, B and C; Box 14.14) and the Model for End-stage Liver Disease (MELD; Box 14.15), based on serum bilirubin, creatinine and INR, which is widely used as a predictor of mortality in patients awaiting liver transplantation. Modifications of the MELD score (e.g. UKELD) are used in some countries.

Gut–liver axis

The liver is exposed to gut-derived bacterial components that have little consequence in health, as an effective gut barrier limits the amount of bacterial components transported to the liver. In advanced liver disease, the intestinal barrier function is compromised due to changes in gut motility, an increase in intestinal permeability, and suppression of gut immunological functions. This leads to bacteria and components entering the portal circulation and being transported to the liver, activating Toll-like receptors and producing an inflammatory response. This cross-talk between the intestinal microbiota and the liver is referred to as the gut–liver axis; it is seen as a key pathophysiological mechanism in the progression of liver disease and development of the complications of cirrhosis. Antibiotics and non-selective β-blockers intercept the gut–liver axis by blocking bacterial translocation, which is likely to account for their beneficial effects in reducing portal pressure, variceal haemorrhage and spontaneous bacterial peritonitis. However, absorbable antibiotics will lead to the selection of resistant bacteria. Rifaximin, a poorly absorbed antibiotic used for encephalopathy, specifically affects the gut flora and has a low risk for inducing resistance; it may therefore have a role in this indication.

Liver transplantation

This is the only established treatment for advanced liver disease. Shortage of donors is a major problem in all developed countries and in some, such as Japan or South Korea, living related donors form the majority.

Indications

These include:

The timing of transplantation depends on donor availability. All patients with end-stage cirrhosis (Child's grade C; MELD score ≥20; UKELD score ≥49) and those with debilitating symptoms should be referred to a transplant centre. In addition, specific extrahepatic complications of cirrhosis, even with preserved liver function, such as hepatopulmonary syndrome and porto-pulmonary hypertension, can be reversed by transplantation.

• Primary biliary cholangitis. Patients should be transplanted when their serum bilirubin is persistently >100 µmol/L or when they have symptoms such as intractable pruritus.

• Chronic hepatitis B if HBV DNA-negative or levels are falling with therapy. Following transplantation, recurrence of hepatitis is prevented by hepatitis B immunoglobulin and nucleoside analogues in combination (see pp. 243–244).

• Chronic hepatitis C. This is the most common indication. Universal HCV re-infection occurs with varying severity and cirrhosis occurs in 10–20% at 5 years. The new antiviral drugs are highly likely to improve these figures greatly.

• Autoimmune hepatitis. In patients who have failed to respond to medical treatment, the disease can recur.

• Alcoholic liver disease. Well-motivated patients who have stopped drinking without improvement of liver disease are offered a transplant, with frequent counselling. It has been shown that transplantation may represent life-saving treatment in patients with severe alcoholic hepatitis who are not responding to medical therapy. However, further studies are awaited.

• Primary metabolic disorders. Examples are Wilson's disease, hereditary haemochromatosis and α1-antitrypsin deficiency.

• NASH cirrhosis. Now one of the most common causes of chronic liver disease in developed countries, this is likely to become the most frequent indication for transplantation.

• Other conditions, such as primary sclerosing cholangitis (PSC), polycystic liver disease, and metabolic diseases such as primary oxaluria.

Preparation for surgery

Pre-transplant work-up includes confirmation of the diagnosis, ultrasound and cross-sectional imaging, and radiological demonstration of the hepatic arterial and biliary trees, as well as assessment of cardiorespiratory and renal status. In view of the ethical and financial implications of transplantation, regular psychosocial, and possibly psychiatric, support is vital.

The donor should be ABO-compatible (HLA matching is not necessary) and have no evidence of active sepsis, malignancy, or HIV, HBV or HCV infection. Younger donors (<50 years) experience better graft function. The donor liver is cooled and stored on ice; its preservation time may be up to 20 hours. The recipient operation takes approximately 8 hours and rarely requires a large blood transfusion. Cadaveric donor livers (from heart-beating or non-heart-beating donors) may consist of whole graft, split grafts (for two recipients) or reduced grafts. Live donors may be healthy individuals or patients with, for example, familial amyloid polyneuropathy, whose livers can be transplanted into others (domino transplant). The mortality of right lobe donors is between 1 in 200 and 1 in 400.

The operative mortality is low and most postoperative deaths occur in the first 3 months. Sepsis and haemorrhage can be serious complications. Opportunistic infections occur owing to immunosuppression. Various immunosuppressive agents have been used, but tacrolimus – alone or in combination with azathioprine or mycophenolate mofetil, steroids, sirolimus and microemulsified ciclosporin are the most common.

Complications and effects of cirrhosis

These are shown in Box 14.16.

image Portal hypertension

The portal vein is formed by the union of the superior mesenteric and splenic veins. Normal pressure is 5–8 mmHg with only a small gradient across the liver to the hepatic vein, in which blood is returned to the heart via the inferior vena cava. Portal hypertension is classified according to the site of obstruction:

As portal pressure rises above 10–12 mmHg, the compliant venous system dilates and collaterals form within the systemic venous system. The main sites of collaterals are the gastro-oesophageal junction, rectum, left renal vein, diaphragm, retroperitoneum and the anterior abdominal wall via the umbilical vein.

The collaterals at the gastro-oesophageal junction (varices) are superficial and tend to rupture. Portosystemic anastomoses at other sites rarely cause symptoms. Rectal varices are found frequently (30%) if looked for and can be differentiated from haemorrhoids, which are lower in the anal canal. The microvasculature of the gut becomes congested, giving rise to portal hypertensive gastropathy and colopathy, in which there is punctate erythema and erosions, which can bleed.

image Aetiology

The most common cause is cirrhosis (Box 14.17). Others are described below.

Prehepatic causes

Extrahepatic blockage due to portal vein thrombosis can be caused by congenital portal venous abnormalities, neonatal sepsis of the umbilical vein, or inherited prothrombotic conditions, such as factor V Leiden or primary myeloproliferative disorders with or without JAK2 mutations (see p. 97).

Patients present with gastrointestinal bleeding, often at a young age. They have normal liver function, and prognosis following bleeding is therefore excellent.

The portal vein blockage can be identified by ultrasound with Doppler imaging; CT and MR angiography are also used.

Treatment for variceal bleeding is usually repeated endoscopic therapy or non-selective beta-blockade. Splenectomy is only performed if there is isolated splenic vein thrombosis. Anticoagulation prevents further thrombosis and intestinal infarction, and does not increase the risk of bleeding.

image Clinical features

Patients are often asymptomatic, the only clinical evidence being splenomegaly, although features of chronic liver disease may exist (see pp. 447–448).

image Variceal haemorrhage

Approximately 90% of patients with cirrhosis will develop gastro-oesophageal varices over 10 years, but only one-third of these will bleed. Bleeding is likely to occur with large varices, or those with red signs at endoscopy, and in severe liver disease.

image Management

Management can be divided into:

Despite the therapeutic techniques available, prognosis ultimately depends on the severity of the underlying liver disease; overall 6-week mortality from variceal haemorrhage is 15–25%, reaching 50% in Child's grade C.

Initial management of acute variceal bleeding

See Figure 14.23, and also the general management of gastrointestinal haemorrhage on page 385.

image
Figure 14.23 Management of gastrointestinal haemorrhage due to oesophageal varices. TIPS, transjugular intrahepatic portosystemic shunt.

Urgent endoscopy

Endoscopy (Fig. 14.24) should be performed to confirm the diagnosis and to exclude bleeding from other sites (e.g. gastric ulceration) and portal hypertensive gastropathy/gastric antral vascular ectasia (GAVE). The latter describes chronic gastric congestion, punctate erythema and gastric erosions, which may contribute to chronic anaemia. Portal hypertensive gastropathy and GAVE are distinct entities; management of portal hypertensive gastropathy is centred on reduction in portal pressures with β-blockers, whereas treatment of GAVE is endoscopic and uses various ablative techniques.

image
Figure 14.24 Endoscopic views of oesophageal varices. A. Gross varices. B. Blood spurting from a varix. C. Following a recent bleed. D. Varices with a band in place (arrowed). (A, C and D Courtesy of Dr Peter Fairclough.)

Other measures

Vasoconstrictor therapy

This is used to restrict portal inflow by splanchnic arterial constriction and has shown benefit when used in combination with endoscopic techniques.

Management of an acute rebleed

Rebleeding occurs in about 15–20% within 5 days. The source should be established by endoscopy and is sometimes due to ulceration or slippage of a ligation band. Endoscopy should be performed once only to control rebleeding. If haemostasis cannot be achieved, then transjugular intrahepatic portocaval shunting will be necessary.

Prophylactic long-term measures

Non-selective beta-blockade

Oral propranolol or carvedilol to reduce the resting pulse rate by 25% decreases portal pressure. Portal inflow is reduced by a decrease in cardiac output (β1) and by blockade of β2 vasodilator receptors on the splanchnic arteries, leaving an unopposed vasoconstrictor effect. Significant reduction of hepatic venous pressure gradient (HVPG; measured by hepatic vein catheterization) is associated with very low rates of rebleeding, particularly if <12 mmHg. Data have emerged demonstrating that additional α1-adrenergic blockade, causing vasodilatation with carvedilol, may increase the number of patients with a reduction in hepatic venous pressure gradient compared to propranolol.

Prophylactic measures (primary prophylaxis)

Patients with cirrhosis and significant varices that have not bled should be prescribed non-selective β-blockers. This reduces the chances of upper gastrointestinal bleeding by approximately 50%, may increase survival, and is cost-effective. If there are contraindications, variceal banding is an option.

image Ascites

Ascites, fluid within the peritoneal cavity, is a common complication of cirrhosis. Several factors underlie its pathogenesis:

In patients with ascites, urine sodium excretion rarely exceeds 5 mmol in 24 hours. Loss of sodium from extrarenal sites accounts for approximately 30 mmol in 24 hours. Under these circumstances, a normal daily sodium intake of 120–200 mmol results in a positive sodium balance of approximately 90–170 mmol in 24 hours (equivalent to 600–1300 mL of fluid retained).

image Investigations

A diagnostic aspiration of 10–20 mL of fluid should be obtained for:

The differential diagnosis of ascites is listed in Box 14.19.

image Management

The aim is both to reduce sodium intake and to increase renal sodium excretion, producing a net reabsorption of fluid from the ascites into the circulating volume. The maximum rate at which ascites can be mobilized is 500–700 mL in 24 hours (see below).

The aim of diuretic therapy should be to produce a net loss of fluid approaching 700 mL in 24 hours (0.7 kg weight loss, or 1.0 kg if peripheral oedema is present). Although 60% of patients respond on this regimen, the spironolactone can be increased gradually to 400 mg daily if necessary, providing there is no hyperkalaemia. A loop diuretic, such as furosemide 20–40 mg or bumetanide 0.5 mg or 1 mg daily, is added if response is poor. These loop diuretics have several potential disadvantages, including hyponatraemia, hypokalaemia and volume depletion.

Diuretics should be temporarily discontinued if a rise in serum creatinine occurs, representing over-diuresis and hypovolaemia, or if there is hyperkalaemia or worsening encephalopathy. Hyponatraemia almost always represents haemodilution secondary to a failure to clear free water (usually a marker of reduced renal perfusion), and diuretics should be stopped if the sodium falls below 128 mmol/L. Vaptans (see p. 164), vasopressin V2-receptor antagonists that increase free water clearance, have a small beneficial effect on hyponatraemia and ascites but do not affect mortality, complications of cirrhosis or renal failure; routine use in cirrhosis cannot be recommended.

Paracentesis

This is used to relieve symptomatic tense ascites or when diuretic therapy is insufficient to control accumulation of fluid. The main complications are hypovolaemia and renal dysfunction (post-paracentesis circulatory dysfunction), predominantly due to an accentuation of the arteriolar vasodilatation already present in these patients; this is more likely with >5 L removal and worse liver function. In patients with normal renal function and without hyponatraemia, this is overcome by infusing albumin (8 g/L of ascitic fluid removed). In practice, up to 20 L can be removed over 4–6 hours, with albumin infusion.

Shunts

A TIPS may be inserted to treat resistant ascites, providing there is no spontaneous portosystemic encephalopathy and there is minimal disturbance of renal function. Frequency of paracentesis and diuretic use is reduced and nutrition is enhanced. Survival may also improve.

A peritoneo-bladder conduit, by means of an implantable, rechargeable, battery-powered pump, has been developed for use in patients with advanced cirrhosis and resistant ascites (alfapump®). This removes ascites from the peritoneal cavity into the urinary bladder, to be eliminated through urination. Early studies have shown a reduction in the need for large-volume paracentesis but several complications, including pain and infection, occur.

image Spontaneous bacterial peritonitis

Spontaneous bacterial peritonitis (SBP) represents a serious complication that is an indication for referral for transplant assessment; it occurs in up to 18% of patients with ascites who have undergone a decompensation. The infecting organisms gain access to the peritoneum by haematogenous spread; most are Escherichia coli, Klebsiella or enterococci. The condition should be suspected in any patient with ascites who deteriorates, as pain and pyrexia are frequently absent. Diagnostic aspiration should always be performed. A raised neutrophil count in ascites is sufficient evidence alone to start immediate treatment. A broad-spectrum antibiotic is used, with subsequent alteration according to culture results in combination with infusions of human albumin solution. Evidence has emerged that non-selective β-blockers should be stopped following diagnosis of SBP, as prescription increases the risk of renal impairment. Mortality is 10–15%. Recurrence is common (70% within a year) and secondary prevention – for example, with norfloxacin 400 mg daily – prolongs survival. Primary prophylaxis of SBP in patients with ascites protein <10 g/L or severe liver disease may prevent hepatorenal syndrome and improve survival.

image Portosystemic encephalopathy

Portosystemic encephalopathy (PSE) is a chronic neuropsychiatric syndrome that is secondary to cirrhosis. Acute encephalopathy can occur in acute hepatic failure (see p. 462). PSE can arise in portal hypertensive patients due to spontaneous ‘shunting’, or in those with surgical or TIPS shunts.

image Pathogenesis

In cirrhosis, the portal blood bypasses the liver via collaterals, and ‘toxic’ metabolites pass directly to the brain to produce encephalopathy. Ammonia-induced alteration of brain neurotransmitter balance, especially at the astrocyte–neurone interface, is considered to be the leading pathophysiological mechanism. Ammonia is produced by the breakdown of protein by intestinal bacteria. Other implicated substances are free fatty acids and mercaptans; accumulation of false neurotransmitters (octopamine) or activation of the γ-aminobutyric acid (GABA) inhibitory neurotransmitter system may also be responsible. Increased blood levels of aromatic amino acids (tyrosine and phenylalanine) and reduced branched-chain amino acids (valine, leucine and isoleucine) also occur. The factors precipitating PSE are shown in Box 14.20.

image Clinical features

An acute onset often has a precipitating factor (Box 14.20). The patient becomes increasingly drowsy and comatose.

Chronically, there is a disorder of personality, mood and intellect, with a reversal of normal sleep rhythm. These changes may fluctuate and a collateral history should be obtained. The patient is irritable, confused and disorientated, and has slow, slurred speech. General features include nausea, vomiting and weakness. There is hyper-reflexia and increased tone. Coma occurs as the encephalopathy becomes more marked. Convulsions are very rare, but if they do occur, other causes must be considered.

Signs include:

image Renal failure (hepatorenal syndrome)

The hepatorenal syndrome typically occurs in patients with advanced cirrhosis, portal hypertension, jaundice and ascites. The urine output is low with a low urinary sodium concentration, a maintained capacity to concentrate urine (i.e. intact tubular function) and almost normal renal histology. The renal failure is therefore described as ‘functional’. It is often precipitated by over-vigorous diuretic therapy, NSAIDs, diarrhoea, paracentesis and infection, particularly spontaneous bacterial peritonitis.

The mechanism is similar to that of ascites, with extreme peripheral vasodilatation leading to decreased effective blood volume and consequent hypotension (see pp. 472–473). This causes increased plasma renin, aldosterone, noradrenaline (norepinephrine) and vasopressin, leading to renal vasoconstriction. There is an increased pre-glomerular vascular resistance that causes blood to be directed away from the renal cortex. This leads to a reduced glomerular filtration rate and plasma renin remains high. Salt and water retention occurs, with reabsorption of sodium from the renal tubules.

Eicosanoids have been incriminated in the pathogenesis, supported by precipitation of the syndrome by inhibitors of prostaglandin synthase, such as NSAIDs.

Diuretic therapy should be stopped and intravascular hypovolaemia corrected, preferably with albumin. Terlipressin or noradrenaline with intravenous albumin improves renal function in approximately 50%. Liver transplantation is the best option. In patients who are candidates for transplantation, haemodialysis can be used as a bridging option but is frequently difficult to perform, and survival is generally limited by the severity of the hepatic failure.

Hepatopulmonary syndrome

This is hypoxaemia in patients with advanced liver disease due to intrapulmonary vascular dilatation with no evidence of primary pulmonary disease. The patients have features of cirrhosis with spider naevi and clubbing, as well as cyanosis. Most are asymptomatic, but with more severe disease, patients are breathless on standing. Transthoracic echocardiography shows intrapulmonary shunting, and arterial blood gases confirm hypoxaemia. These changes are improved with liver transplantation.

Porto-pulmonary hypertension

This occurs in 1–2% of patients with cirrhosis and portal hyper­tension. It may respond to medical therapy (e.g. intravenous epoprostenol, or oral bosentan and sildenafil). Severe pulmonary hypertension is a contraindication to liver transplantation.

Primary hepatocellular carcinoma

This is discussed on page 485.

Further reading

Hadjihambi A, Khetan V, Jalan R. Pharmacotherapy for hyperammonemia. Expert Opin Pharmacother 2014; 15:1685–1695.

Kimer N, Krag A, Møller S et al. Systematic review with meta-analysis: the effects of rifaximin in hepatic encephalopathy. Aliment Pharmacol Ther 2014; 40:123–132.

Rodriguez-Roisin R, Krowka MJ. Hepatopulmonary syndrome. N Engl J Med 2008; 358:2378–2387.

Turon F, Casu S, Hernández-Gea V et al. Variceal and other portal hypertension related bleeding. Best Pract Res Clin Gastroenterol 2013; 27: 649–664.

Wong F, Nadim MK, Kellum JA et al. Working party proposal for a revised classification system of renal dysfunction in patients with cirrhosis. Gut 2011; 60:702–709.

Types of cirrhosis

image Alcoholic cirrhosis

This is discussed in the section on alcoholic liver disease (see pp. 480–482).

image Primary biliary cholangitis

Primary biliary cholangitis (PBC; Fig. 14.25) is a chronic disorder with progressive destruction of small bile ducts, leading to cirrhosis. Women aged 40–50 years constitute 90% of patients. PBC is diagnosed increasingly frequently in its milder forms. The prevalence is approximately 7.5 per 100 000, with a 1–6% increase in first-degree relatives. PBC has been called ‘chronic non-suppurative destructive cholangitis’, a term more descriptive of the early lesion, which emphasizes the fact that true cirrhosis occurs only in the later stages.

image
Figure 14.25 Primary biliary cholangitis. Portal tract inflammation with lymphocytes and plasma cells (×10).

image Primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by fibrosing inflammatory destruction of both the intra- and extrahepatic bile ducts. In 75% of patients, PSC is associated with inflammatory bowel disease (usually ulcerative colitis); it is not unusual for PSC to predate the onset of inflammatory bowel disease. The causes are unknown but genetic susceptibility to PSC is associated with the HLA-A1-B8-DR3 haplotype. The autoantibody pANCA (anti-neutrophil cytoplasmic antibody) is found in the serum of 60% of cases. Seventy per cent of patients are men and the average age of onset is approximately 40 years. Secondary PSC is seen in patients with HIV and cryptosporidium (see p. 350) and may follow ketamine misuse.

image Clinical features

With increasing screening of patients with inflammatory bowel disease, PSC is detected at an asymptomatic phase with abnormal liver biochemistry, usually a raised serum alkaline phosphatase. Symptomatic presentation is usually with fluctuating pruritus, jaundice and cholangitis.

image Diagnosis

The typical biliary changes associated with PSC may be identified by MRCP. The cholangiogram characteristically shows irregularity of calibre of both intra- and extrahepatic ducts, although either may be involved alone (Fig. 14.26).

image
Figure 14.26 Primary sclerosing cholangitis. An endoscopic cholangiogram showing the typical features of primary sclerosing cholangitis. There are calibre irregularities of the intrahepatic ducts (IHD). There is also minor stricturing of the extrahepatic ducts at the confluence between the common bile duct (CBD) and the common hepatic duct (CHD).
image Management

PSC is a slowly progressive lesion (symptoms and biochemical tests may fluctuate), which ultimately leads to liver cirrhosis and associated decompensation. Recurrent cholangitis may be a feature before the onset of cirrhosis. Cholangiocarcinoma occurs in up to 15% of patients (see pp. 485–486 and 498).

The only proven treatment is liver transplantation. The bile acid, ursodeoxycholic acid, has been evaluated extensively but there is no evidence of benefit. High-dose therapy (30 mg/kg) may be deleterious. In a small minority, the dominant lesion is sited in the extrahepatic ducts (Fig. 14.26). Such lesions may be amenable to endoscopic biliary intervention with balloon dilatation and temporary stent placement (see p. 497).

image Secondary biliary cirrhosis

Cirrhosis can result from prolonged (for months) large duct biliary obstruction. Causes include bile duct strictures, gallstones and sclerosing cholangitis. An ultrasound examination and MRCP, sometimes followed by ERCP or percutaneous transhepatic cholangiography (where the ducts are cannulated under ultrasound guidance through the skin) if cannulation is difficult, is performed to outline the ducts, and any remedial cause is treated.

image Hereditary haemochromatosis

Hereditary haemochromatosis (HH; see also p. 445) is an inherited disease characterized by excess iron deposition in various organs, leading to eventual fibrosis and functional organ failure. There are four main types of inherited disorders:

All are transmitted by an autosomal recessive gene, apart from the ferroportin iron overload, which is dominantly transmitted.

HH has a prevalence in Caucasians (homozygotes) of 1 in 400, but very variable phenotypic expression and a heterozygote (carrier) frequency of 1 in 10. It is the most common single-gene disorder in Caucasians.

image Aetiology

Between 85% and 90% of patients with overt HH are homozygous for the Cys 282 Tyr (C282Y mutation): that is, type 1 HFE. A second mutation (His 63 Asp, H63D) occurs in about 25% of the population and is in complete linkage disequilibrium with Cys 282 Tyr.

Another form of haemochromatosis (type 3) occurs in southern Europe and is associated with TfR2, a transferrin receptor isoform. The other types, ferroportin-related (type 4) and juvenile forms (types 2A and 2B), are much rarer.

Dietary intakes of iron and chelating agents (ascorbic acid) may be relevant. Iron overload may be present in alcoholics; alcohol excess per se does not cause HH, although there is a history of excess alcohol intake in 25% of patients.

Mechanism of damage

The HFE gene protein interacts with the transferrin receptor 1, which is a mediator in intestinal iron absorption (see Fig. 16.8). Iron is taken up by the mucosal cells inappropriately, exceeding the binding capacity of transferrin.

Hepcidin, a protein synthesized in the liver (Fig. 14.27), is central to the control of iron absorption; it is increased in iron deficiency states and decreased with iron overload. The mutations described above disrupt hepcidin expression, thereby internalizing ferroportin and leading to uninhibited iron overload.

image
Figure 14.27 The circulation of iron from the duodenal enterocyte to and from the liver, red cells and reticuloendothelial macrophages. Some 1–2 g of iron is absorbed from the intestine (see Fig. 16.8) and circulates bound to transferrin. The reticuloendothelial cells clear old erythrocytes and release iron to circulate and be stored as ferritin in the liver. The liver is the major site of production of the peptide hormone, hepcidin. Hepcidin blocks release of iron from the erythrocytes and macrophages by degrading the iron exporter transferrin. Fe, iron. (Modified from Fleming RE, Ponka P. Iron overload in human disease. N Engl J Med 2012; 366:348–359, with permission.)

Hepatic expression of the hepcidin gene is decreased in HFE haemochromatosis, facilitating liver iron overload. Excess iron is then gradually taken up by the liver and other tissues over a long period. It seems likely that it is the iron itself that precipitates fibrosis.

image Pathology

In symptomatic patients, the total body iron content is 20–40 g, compared with 3–4 g in a normal person. The iron content is particularly increased in the liver (Fig. 14.28) and pancreas (50–100 times normal) but is also increased in other organs (e.g. the endocrine glands, heart and skin).

image
Figure 14.28 Cirrhotic nodule in haemochromatosis. Note the iron overload (blue) (Perls, ×25).

In established cases, the liver shows extensive iron deposition and fibrosis. Early in the disease, iron is deposited in the periportal hepatocytes (in pericanalicular lysosomes). Later, it is distributed widely throughout all acinar zones, biliary duct epithelium, Kupffer cells and connective tissue. Cirrhosis is a late feature.

image Complications

Some 30% of people with cirrhosis will develop primary hepatocellular carcinoma (HCC; Fig. 14.29). HCC has been described only very rarely in non-cirrhotic patients in whom the excess iron stores have been removed. Early diagnosis is vital.

image
Figure 14.29 Hepatocellular carcinoma. (Haematoxylin and eosin, ×25.)

image Wilson's disease (progressive hepatolenticular degeneration)

Dietary copper is normally absorbed from the stomach and upper small intestine. Copper is transported to the liver loosely bound to albumin; in the liver, it is incorporated into apocaeruloplasmin, forming caeruloplasmin, a glycoprotein synthesized in the liver, and secreted into the blood. The remaining copper is normally excreted in the bile and excreted in faeces.

Wilson's disease is a very rare inborn error of copper metabolism that results in copper deposition in various organs, including the liver, the basal ganglia of the brain and the cornea. It is potentially treatable and all young patients with liver disease must be screened for this condition.

image Alpha1-antitrypsin deficiency

A deficiency of alpha1-antitrypsin (α1-AT; see also p. 1081) is sometimes associated with liver disease and pulmonary emphysema (particularly in smokers). Part of a family of serine protease inhibitors, or serpin superfamily, α1-AT is a glycoprotein. Deficiency of α1-AT is a genetic disorder and 1 in 10 northern Europeans carries an abnormal gene.

The protein is a 394-amino acid 52 kDa acute phase protein that is synthesized in the liver and constitutes 90% of the serum α1-globulin seen on electrophoresis. Its main role is to inhibit the proteolytic enzyme, neutrophil elastase.

The gene is located on chromosome 14. The genetic variants of α1-AT are characterized by their electrophoretic mobilities as medium (M), slow (S) or very slow (Z). The normal genotype is protease inhibitor MM (PiMM), the homozygote for Z is PiZZ, and the heterozygotes are PiMZ and PiSZ. S and Z variants are due to a single amino acid replacement of glutamic acid at positions 264 and 342 of the polypeptide, respectively. This results in decreased synthesis and secretion of the protein by the liver as protein–protein interactions occur between the reactive centre loop of one molecule and the β-pleated sheet of a second (loop sheet polymerization).

How this causes liver disease is uncertain. It is postulated that failure of secretion of the abnormal protein leads to an accumulation in the liver, causing liver damage.

image Clinical features

The majority of patients with clinical disease are homozygotes with a PiZZ phenotype. Some may present in childhood and a few require transplantation. Approximately 10–15% of adult patients will develop cirrhosis, usually over the age of 50 years, and 75% will have respiratory problems. Approximately 5% of patients die of their liver disease. Heterozygotes (e.g. PiSZ or PiMZ) may develop liver disease but the risk is small.

image Management

There is no treatment, apart from dealing with the complications of liver disease. Patients with hepatic decompensation should be assessed for liver transplantation, and should stop smoking (see p. 1081).

Further reading

Andrews NC. Closing the iron gate. N Engl J Med 2012; 366:376–370.

Bacon BR, Adams PC, Kowdley KV et al. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 2011; 54:328–343.

European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Wilson disease. J Hepatol 2012; 56:671–685.

Gideon M et al. Primary sclerosing cholangitis. Lancet 2013; 382:1587–1599.

Pietrangelo A. Hereditary haemochromatosis: pathogenesis, diagnosis, and treatment. Gastroenterology 2010; 139:393–408.

Selmi C, Bowlus CL, Gershwin ME et al. Primary biliary cirrhosis. Lancet 2011; 377:1600–1609.

Alcoholic Liver Disease

This section describes the pathology and clinical features of alcoholic liver disease. The amounts needed to produce liver damage, alcohol metabolism, and other clinical effects of alcohol are described on pages 217–218.

Ethanol is metabolized in the liver by two pathways, resulting in an increase in the NADH/NAD ratio. The altered redox potential causes increased hepatic fatty acid synthesis with decreased fatty acid oxidation; both events lead to hepatic accumulation of fatty acid, which is then esterified to glycerides.

The changes in oxidation–reduction also impair carbohydrate and protein metabolism and are the cause of the centrilobular necrosis of the hepatic acinus that is typical of alcohol damage. TNF-α release from Kupffer cells causes the release of reactive oxygen species, leading, in turn, to tissue injury and fibrosis.

Acetaldehyde is formed by the oxidation of ethanol, and its effect on hepatic proteins may well be a factor in producing liver cell damage. The exact mechanism of alcoholic hepatitis and cirrhosis is unknown, but since only 10–20% of people who drink heavily will develop cirrhosis, a genetic predisposition is recognized. Immunological mechanisms have also been proposed, with the release of cytokines, particularly IL-8, which is a neutrophil chemoattractant; infiltration with neutrophils is a feature of alcoholic hepatitis.

Alcohol can enhance the effects of the toxic metabolites of drugs (e.g. paracetamol) on the liver, as it induces microsomal metabolism via the microsomal ethanol oxidizing system (MEOS; see p. 217).

image Pathology

Alcohol can produce a wide spectrum of liver disease from fatty change to hepatitis and cirrhosis.

Fatty liver

The metabolism of alcohol invariably produces fat in the liver (Fig. 14.30), mainly in zone 3. This is minimal with small amounts of alcohol, but with larger amounts the cells become swollen with fat (steatosis). There is no liver cell damage. The fat disappears on stopping alcohol. Steatosis is also seen in non-alcoholic fatty liver disease (NAFLD) (see p. 465).

image
Figure 14.30 Liver steatosis (×10).

In some cases, collagen is laid down around the central hepatic veins (perivenular fibrosis) and this can sometimes progress to cirrhosis without a preceding hepatitis. Alcohol directly affects stellate cells, transforming them into collagen-producing myofibroblast cells (see p. 440).

Alcoholic hepatitis

In addition to fatty change, there is infiltration by polymorphonuclear leucocytes and hepatocyte necrosis, mainly in zone 3. Dense cytoplasmic inclusions called Mallory bodies are sometimes seen in hepatocytes and giant mitochondria are also a feature. Mallory bodies are suggestive of, but not specific for, alcoholic damage, as they can be found in other liver disease, such as Wilson's disease and primary biliary cholangitis. If alcohol consumption continues, alcoholic hepatitis may progress to cirrhosis.

Alcoholic cirrhosis

This is classically of the micronodular type but a mixed pattern is also seen accompanying fatty change, and evidence of pre-existing alcoholic hepatitis may be present.

image Clinical features
Fatty liver

There are often no symptoms or signs. Vague abdominal symptoms of nausea, vomiting and diarrhoea are due to the more general effects of alcohol on the gastrointestinal tract. Hepatomegaly, sometimes huge, can occur, together with other features of chronic liver disease.

Alcoholic cirrhosis

This represents the final stage of liver disease from alcohol use. Nevertheless, patients can be very well with few symptoms. On examination, there are usually signs of chronic liver disease (p. 448). The diagnosis is confirmed by liver biopsy.

The patient usually presents with one of the complications of cirrhosis. In many cases, there are features of alcohol dependency (see pp. 921–922), as well as evidence of involvement of other systems, such as polyneuropathy.

image Management and prognosis
General management

All patients should stop drinking alcohol. Delirium tremens (a withdrawal symptom) is treated with diazepam. Intravenous thiamine should be given empirically to prevent Wernicke–Korsakoff encephalopathy. Bed rest is necessary, along with a diet high in protein and vitamin supplements. Dietary protein sometimes needs to be limited because of encephalopathy. Patients must be advised to participate in alcohol cessation programmes. The likelihood of abstention is dependent on many factors, particularly social and family ones.

Alcoholic hepatitis

In severe cases, the patient requires admission to hospital. Nutrition must be maintained with enteral feeding, if necessary, and vitamin supplementation given. Steroid therapy has been widely used in patients with a discriminant function score of >32 but a recent multicentre UK study, which included over 1000 patients, suggested that there was no survival benefit.

Discriminant function (DF)

DF=[4.6×prothrombin time above control in seconds] + bilirubin (mg/dL)Bilirubin mmol/L÷17 to convert to mg/dL.Severe= > 32.

image

The response to steroid therapy can also be evaluated by the Lille score (>0.45 indicates poor response to steroids, which can therefore be stopped) and the Glasgow score (Boxes 14.21 and 14.22). A Glasgow score of >9 indicates that steroids are necessary because at >9 the 28-day mortality is 75%, while at <9 it is 50%. The MELD score (see p. 467) is also used but does not indicate which patients need steroid therapy.

image Box 14.21

Lille score for alcoholic hepatitis

(Calculator at http://www.lillemodel.com)

R = 3.19 − (0.101 × age in years) + (0.147 × albumin on admission in g/L) + (0.0165 × change in bilirubin level from day 0 to day 7 in µmol/L) − (0.206 × renal insufficiency [0 if absent, 1 if present]a ) − (0.0065 × bilirubin day 0 in µmol/L) − (0.0096 × INR)

A score of <0.16 indicates a 96% chance of survival at 28 days; ≥0.56 indicates a 55% chance of survival at 28 days.

Score = EXP(−R)/[1+EXP(−R)]

aCreatinine >115 µmol/L.

Infection must be excluded or concomitantly treated. Treatment for encephalopathy and ascites is commenced. Antifungal prophylaxis should also be used.

Patients are advised to stop drinking for life, as this is undoubtedly a pre-cirrhotic condition. The prognosis is variable and, despite abstinence, the liver disease is progressive in many patients. Granulocyte-colony stimulating factor (G-CSF) for 5 days improves 90-day survival in preliminary studies.

In severe cases, the mortality is at least 50%; with a prothrombin time twice normal, progressive encephalopathy and acute kidney injury, the mortality approaches 90%. Early transplantation for patients with severe alcoholic hepatitis has a survival rate of 78%, compared with 32% of those not transplanted. Unfortunately, many return to drinking.

Alcoholic cirrhosis

The management of cirrhosis is described on page 467. Again, all patients are advised to stop drinking for life. Abstinence from alcohol results in an improvement in prognosis, with a 5-year survival of 90%, but with continued drinking this falls to 60%. In advanced disease (i.e. jaundice, ascites and haematemesis) the 5-year survival rate falls to 35%, most of the deaths occurring in the first year. Liver transplantation results in good survival; recurrence of cirrhosis due to recidivism is rare. Patients often sign a contract with their clinicians regarding their abstinence, both before and after transplantation.

A trial of abstention to establish whether liver disease can improve is mandatory, but transplantation should not be denied if the patient continues to deteriorate. Specific follow-up regarding alcohol use is recommended.

HCC is a complication, particularly in men.

Further reading

Thursz MR, Richardson P, Allison M et al. Prednisolone or pentoxifylline for alcoholic hepatitis. N Engl J Med 2015; 372:1619–1628.

Budd–Chiari Syndrome

In this condition, there is obstruction to the venous outflow of the liver owing to occlusion of the hepatic vein. In one-third of patients the cause is unknown, but specific causes include hypercoagulability states (e.g. paroxysmal nocturnal haemoglobinuria, polycythaemia vera) or thrombophilia (see p. 575), taking the contraceptive pill, or leukaemia. Other causes include occlusion of the hepatic vein owing to posterior abdominal wall sarcomas, renal or adrenal tumours, hepatocellular carcinoma, hepatic infections (e.g. hydatid cyst), congenital venous webs, radiotherapy or trauma to the liver.

image Clinical features

The acute form presents with abdominal pain, nausea, vomiting, tender hepatomegaly and ascites (a fulminant form occurs particularly in pregnant women). In the chronic form, there is enlargement of the liver (particularly the caudate lobe), mild jaundice, ascites, a negative hepatojugular reflux, and splenomegaly with portal hypertension.

image Investigations

Investigations show a high protein content in the ascitic fluid and characteristic liver histology with centrizonal congestion, haemorrhage, fibrosis and cirrhosis. Ultrasound, CT or MRI will demonstrate hepatic vein occlusion with diffuse abnormal parenchyma on contrast enhancement. The caudate lobe is spared because of its independent blood supply and venous drainage. There may be compression of the inferior vena cava. Pulsed Doppler sonography or colour Doppler is useful, as it shows abnormalities of flow in the hepatic vein. Thrombophilia screening is mandatory. Multiple defects of coagulation occur. Thrombosis of the portal vein is present in 2% of patients.

image Differential diagnosis

A similar clinical picture can be produced by inferior vena caval obstruction, right-sided cardiac failure or constrictive pericarditis, and appropriate investigations should be performed.

image Management

In the acute situation, thrombolytic therapy can be given. Ascites should be treated, as should any underlying cause (e.g. polycythaemia). Congenital webs should be treated radiologically or resected surgically. A TIPS is the treatment of choice, as caval compression does not prejudice the efficacy of TIPS. Surgical portocaval shunts are reserved for those who fail this treatment, providing there is no caval obstruction or severe caval compression when a caval stent can be inserted. Liver transplantation is the first-choice treatment for chronic Budd–Chiari syndrome and for the fulminant form. Life-long anticoagulation is mandatory following TIPS and transplantation.

image Prognosis

The prognosis depends on the aetiology but some patients can survive for several years.

Further reading

Mancuso A. An update on management of Budd–Chiari syndrome. Ann Hepatol 2014; 13:323–326.

Hepatic Sinusoidal Obstruction Syndrome

Hepatic sinusoidal obstruction syndrome (SOS; previously known as veno-occlusive disease) is due to injury of the hepatic veins and presents clinically like the Budd–Chiari syndrome. It was originally described in Jamaica, where the ingestion of toxic pyrrolizidine alkaloids in bush tea (made from plants of the genera Senecio, Heliotropium and Crotalaria) caused damage to the hepatic veins. It can be seen in other parts of the world. It also occurs as a complication of chemotherapy and total body irradiation, used before allogeneic bone marrow transplantation. The development of SOS after bone marrow transplantation carries a high mortality. Treatment is supportive, with control of ascites and hepatocellular failure. TIPS has been used in a few cases. Defibrotide is recommended for prophylactic use before bone marrow transplantation in children and adults with a high risk of SOS (e.g. pre-existing hepatic disease or prior treatment with gemtuzumab ozogamicin).

Fibropolycystic Diseases

These diseases are usually inherited and lead to the presence of cysts or fibrosis in the liver, kidney and occasionally the pancreas, and other organs.

image Polycystic disease of the liver

Multiple cysts can occur in the liver as part of autosomal dominant polycystic disease of the kidney (see pp. 789–790). These cysts are usually asymptomatic but occasionally cause abdominal pain and distension. Liver function is normal and complications such as oesophageal varices are very rare. The prognosis is excellent and depends on the kidney disease.

image Solitary cysts

These are usually found by chance during imaging and are mainly asymptomatic.

image Congenital hepatic fibrosis

In this rare condition, the liver architecture is normal but there are broad collagenous fibrous bands extending from the portal tracts. Congenital hepatic fibrosis is often inherited as an autosomal recessive condition but can also occur sporadically. It usually presents in childhood with hepatosplenomegaly, and portal hypertension is common. It may present later in life and can be misdiagnosed as cirrhosis.

A wedge biopsy of the liver may be required to confirm the diagnosis. The outlook is good and the condition should be distinguished from cirrhosis. Patients who bleed do well after endoscopic therapy of varices (or a portocaval anastomosis) because of their good liver function.

image Congenital intrahepatic biliary dilatation (Caroli's disease)

In this rare, non-familial disease there are saccular dilatations of the intrahepatic or extrahepatic ducts. It can present at any age (although it usually does so in childhood) with fever, abdominal pain and recurrent attacks of cholangitis with Gram-negative septicaemia. Jaundice and portal hypertension are absent. Diagnosis is by ultrasound, percutaneous transhepatic cholangio­graphy and MRCP. There is an increased risk of biliary malignancy.

Liver Abscess

image Pyogenic abscess

Pyogenic abscesses are uncommon; they may be single or multiple. The most common used to be a portal pyaemia from intra-abdominal sepsis (e.g. appendicitis or perforations), but now the aetiology is not known in many cases. In the elderly, biliary sepsis is a common cause. Other causes include trauma, bacteraemia and direct extension from, for example, a perinephric abscess.

The organism found most commonly is E. coli. Streptococcus milleri and anaerobic organisms such as Bacteroides are often seen. Other organisms include Enterococcus faecalis, Proteus vulgaris and Staphylococcus aureus. Often the infection is mixed.

image Clinical features

Some patients are not acutely ill and present with malaise lasting several days or even months. Others can present with fever, rigors, anorexia, vomiting, weight loss and abdominal pain. In these patients, a Gram-negative septicaemia with shock can occur. On examination, there may be little to find. Alternatively, the patient may be toxic, febrile and jaundiced. In such patients, the liver is tender and enlarged, and there may be signs of a pleural effusion or a pleural rub in the right lower chest.

image Investigations

Patients who are not acutely ill are often investigated as a case of ‘pyrexia of unknown origin’ (PUO) and most investigations will be normal. Often, the only clue to the diagnosis is a raised serum alkaline phosphatase.

Imaging

Ultrasound is useful for detecting abscesses. A CT scan may be of value in complex and multiple lesions (Fig. 14.31). A chest X-ray will show elevation of the right hemidiaphragm with a pleural effusion in the severe case. Depending on age, imaging of the colon may be necessary to find the source of the infection.

image
Figure 14.31 CT scan showing liver abscesses. Abscesses are shown in the right lobe of the liver (arrowed), secondary to partial biliary obstruction.

Other Infections of the Liver

Schistosomiasis

Schistosoma mansoni and S. japonicum affect the liver, but S. haematobium rarely does so (see also pp. 312–314). During their life cycle, the ova reach the liver via the venous system and obstruct the portal branches, producing granulomas, fibrosis and inflammation, but not cirrhosis.

image Clinical features and investigations

Clinically, there is hepatosplenomegaly and portal hypertension, which is particularly severe with S. mansoni. In Egypt, there is frequently concomitant chronic hepatitis C infection.

Investigations show a raised serum alkaline phosphatase, and ova can be found in the stools (centrifuged deposits) and in rectal and liver biopsies. Skin tests and other immunological tests often give false results and may also be positive because of past infection.

image Management

Treatment is with praziquantel, but fibrosis still remains with a potential risk of portal hypertension, characteristically pre-sinusoidal due to intense portal fibrosis.

image Hydatid disease

Cysts caused by Echinococcus granulosus are single or multiple. They usually occur in the lower part of the right lobe. The cyst has three layers: an outside layer derived from the host, an intermediate laminated layer, and an inner germinal layer that buds off brood capsules to form daughter cysts (see also pp. 315–316).

image Clinical features and investigations

Clinically, there may be no symptoms or there may be a dull ache and swelling in the right hypochondrium.

Investigations show a peripheral eosinophilia in 30% of cases and usually a positive hydatid complement fixation test or haemagglutination (85%). Plain abdominal X-ray may show calcification of the outer coat of the cyst. Ultrasound and CT scan demonstrate cysts and may show diagnostic daughter cysts within the parent cyst (Fig. 14.32).

image
Figure 14.32 CT scan of liver showing a large hydatid cyst (arrowed). ‘Daughter’ cysts are also shown lying within it.

Liver Tumours

Secondary liver tumours

The most common liver tumour is a secondary (metastatic) tumour, particularly from the gastrointestinal tract (from the distribution of the portal blood supply), breast or bronchus. Secondary liver tumours are usually multiple.

Primary malignant tumours

Primary liver tumours may be benign or malignant, but the most common are malignant.

image Hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide.

image Aetiology

Carriers of HBV and HCV have an extremely high risk of developing HCC. In areas where HBV is prevalent, 90% of patients with this cancer are positive for HBV. Cirrhosis is present in approximately 80% of these patients. The development of HCC is related to the integration of viral HBV DNA into the genome of the host hepatocyte (see p. 456), and to the degree of viral replication (>10 000 copies/mL). The risk of HCC in HCV is higher than in HBV (even higher with both HBV and HCV), despite no viral integration. Unlike HBV infection, cirrhosis is always present in HIV. Primary liver cancer is also associated with other forms of cirrhosis, such as alcoholic cirrhosis, non-alcoholic fatty liver disease (NAFLD)-associated cirrhosis, and haemochromatosis. Males are affected more than females. Other aetiological factors are aflatoxin (a metabolite of a fungus found in groundnuts) and androgenic steroids, and there is a weak association with the contraceptive pill.

image Pathology

The tumour either is single or occurs as multiple nodules throughout the liver. Histologically, it consists of cells resembling hepatocytes. It can metastasize via the hepatic or portal veins to the lymph nodes, bones and lungs.

image Clinical features

The clinical features include weight loss, anorexia, fever, an ache in the right hypochondrium and ascites. The rapid development of these features in a cirrhotic patient is suggestive of HCC. On examination, an enlarged, irregular, tender liver may be felt. Increasingly, due to surveillance, HCC is found without symptoms in patients with cirrhosis.

image Investigations

• Routine liver biochemistry, full blood count, urea and electrolytes.

• Serum α-fetoprotein may be raised, but is normal in at least a third of patients.

• Ultrasound scans show filling defects in 90% of cases.

• Enhanced CT scans (Fig. 14.33) identify HCC but it is difficult to confirm the diagnosis in lesions smaller than 1 cm. An MRI can help to delineate lesions further.

image
Figure 14.33 Hepatocellular carcinoma. A. CT showing cirrhosis with a hepatocellular carcinoma (arrowed). B. T2-weighted MRI of the liver following gadolinium contrast showing a hepatocellular carcinoma.

• Tumour biopsy (see Fig. 14.29), particularly under ultrasonic guidance, is now used less frequently for diagnosis as imaging techniques show characteristic appearances (hypervascularity of the nodule and lack of portal vein washout) and because seeding along the biopsy tract can occur.

image Management and prognosis

See page 638.

image Prevention

Persistent HBV infection, usually acquired after perinatal infection, is a high risk factor for HCC in many parts of the world, such as South-east Asia. Widespread vaccination against HBV is being used and this has reduced the annual incidence of HCC in Taiwan.

image Cholangiocarcinoma

Cholangiocarcinomas are increasing in incidence and can be extrahepatic (see p. 498) or intrahepatic (see p. 638). Intrahepatic adenocarcinomas arising from the bile ducts account for approximately 10% of primary tumours of the liver and biliary tract. They are not associated with cirrhosis or hepatitis B. In the Far East, they may be associated with infestation with Clonorchis sinensis or Opisthorchis viverrini. The clinical features are similar to those of primary HCC, except that jaundice is frequent with hilar tumours, and cholangitis is more common. There is an increased association with inflammatory bowel disease and primary sclerosing cholangitis (see pp. 476–477).

Surgical resection is rarely possible and patients usually die within 6 months. Transplantation is contraindicated, outside of specialized protocols.

Benign tumours

The most common benign tumour is a haemangioma. It is usually small and single but can be multiple and large. Haemangiomas are usually found incidentally on ultrasound, CT or MRI, and have characteristic appearances. They require no treatment.

Hepatic adenomas are associated with oral contraceptives. They can present with abdominal pain or intraperitoneal bleeding. Resection is required only for symptomatic patients, those with tumours >5 cm in diameter, and in those in whom discontinuation of oral contraception does not result in shrinkage of the tumour. Immunohistochemical characteristics are helpful in indicating malignant potential, which is far more common in men.

Further reading

El-Serag HB. Hepatocellular carcinoma. N Engl J Med 2011; 365:1118–1127.

Forner A, Llovet JM, Bruix J et al. Hepatocellular carcinoma. Lancet 2012; 379:1245–1255.

Miscellaneous Conditions of the Liver

image Hepatic mitochondrial injury syndromes

These syndromes – in which there is mitochondrial damage with inhibition of β-oxidation of fatty acids – can be categorized as having the following causes:

• Genetic, with abnormalities that include medium-chain acyl-coenzyme A dehydrogenase deficiency, leading to microsteatosis.

• Toxins leading to liver failure, which include aflatoxin and cerulide (produced by Bacillus cereus); the latter causes food poisoning (see p. 277).

• Drugs (e.g. i.v. tetracycline, valproic acid and nucleoside reverse-transcriptase inhibitors), which can produce a fatal microsteatosis.

• Idiopathic, the best known being fatty liver of pregnancy (see p. 1304) and Reye syndrome. The latter, caused by inhibition of β-oxidation and uncoupling of oxidative phosphorylation in mitochondria, leads in children to an acute encephalopathy and diffuse microvesicular fatty infiltration of the liver. Aspirin ingestion and viral infections have been implicated as precipitating agents. Mortality is about 50%, usually due to cerebral oedema.

image Idiopathic adult ductopenia

This unexplained condition is characterized by pruritus and cholestatic jaundice. Histology of the liver shows a decrease in intrahepatic bile ducts in at least 50% of the portal tracts, together with the features of cholestasis and marked fibrosis or cirrhosis. In most, the disease is progressive and the only treatment is liver transplantation.

image Indian childhood cirrhosis

This condition of children is seen in the Indian subcontinent. The cause is unknown. Eventually, there is development of a micro­nodular cirrhosis with excess copper in the liver.

image Hepatic porphyrias

These are dealt with on page 1290.

image Cystic fibrosis

Cystic fibrosis (see also pp. 1088–1089) mainly affects the lung and pancreas, but patients can develop fatty liver, cholestasis and cirrhosis. The aetiology of the liver involvement is unclear.

image Coeliac disease

Abnormal liver biochemical tests are common in coeliac disease (see also p. 396) and return to normal with a gluten-free diet. A tissue transglutaminase test should be performed if hepatic causes are not found when investigating abnormal liver biochemistry.

Drugs and the Liver

Drug metabolism

The liver is the major site of drug metabolism. Drugs are converted from fat-soluble to water-soluble substances that can be excreted in the urine or bile. This metabolism of drugs is mediated by a group of mixed-function enzymes (see p. 19).

Drug hepatotoxicity

Many drugs impair liver function. When abnormal liver biochemical tests are found, drugs should always be considered as a cause, particularly when other causes have been excluded. Damage to the liver by drugs is usually classified as being either predictable (or dose-related) or non-predictable (not dose-related) (see p. 22). However, there is considerable overlap and at least six mechanisms may be involved in the production of damage:

The predominant mechanism or combination of mechanisms determines the type of liver injury: that is, hepatitic, cholestatic or immunological (skin rashes, fever and arthralgia, i.e. serum-sickness syndrome). Eosinophilia and circulating immune complexes and antibodies are occasionally detected.

When a small amount of hepatotoxic drug whose effect is dose-dependent (e.g. paracetamol) is ingested, a large proportion of it undergoes conjugation with glucuronide and sulphate, while the remainder is metabolized by microsomal enzymes to produce toxic derivatives that are immediately detoxified by conjugation with glutathione. If larger doses are ingested, the former pathway becomes saturated and the toxic derivative is produced at a faster rate. Once the hepatic glutathione is depleted, large amounts of the toxic metabolite accumulate and produce damage (see p. 79).

The ‘predictability’ of drugs to produce damage can, however, be affected by metabolic events preceding their ingestion. For example, chronic alcohol users may become more susceptible to liver damage because of the enzyme-inducing effects of alcohol, or ill or starving patients may become susceptible because of the depletion of hepatic glutathione produced by starvation. Many other factors, such as environmental or genetic effects, may be involved in determining the ‘susceptibility’ of certain patients to certain drugs.

The incidence of drug hepatotoxicity is 14 per 100 000 population with a 6% mortality. It is the most common cause of acute liver failure in the USA. Liver transplantation is used.

Hepatitic damage

The type of damage produced by various drugs is shown in Box 14.23. Most reactions occur within 3 months of starting the drug. Monitoring liver biochemistry in patients on long-term treatment, such as anti-tuberculosis therapy, is mandatory. If a drug is suspected of causing hepatic damage, it should be stopped immediately. Liver biopsy is of limited help in confirming the diagnosis, but occasionally, hepatic eosinophilia or granulomas may be seen. Diagnostic challenge with subtherapeutic doses of the drug is sometimes required after the liver biochemistry has returned to normal, to confirm the diagnosis.

image Box 14.23

Liver damage produced by some drugs

Types of liver damageDrugs
Zone 3 necrosis
Zone 1 necrosisFerrous sulphate
Microvesicular fatSodium valproateTetracyclines
SteatohepatitisNifedipine
Fibrosis
Vascular
Sinusoidal dilatationContraceptive drugsAnabolic steroids
Peliosis hepatis
Veno-occlusivePyrrolizidine alkaloids (Senecio in bush tea)Cytotoxics – cyclophosphamide
Acute hepatitis
Chronic hepatitis
General hypersensitivity
Canalicular cholestasis
Biliary sludgeCeftriaxone
Sclerosing cholangitisHepatic arterial infusion of 5-fluorouracil
Hepatic tumoursPills with high hormone content (adenomas)
Hepatocellular carcinomaContraceptive pillDanazol
Nodular regenerative hyperplasiaAzathioprineSome anti-retroviral therapies

image

NSAID, non-steroidal anti-inflammatory drug. Note: Anti-HIV drugs, e.g. maraviroc, cause hepatic dysfunction.

Individual drugs

Paracetamol

In high doses, paracetamol produces liver cell necrosis (see above). The toxic metabolite binds irreversibly to liver cell membranes. Overdosage is discussed on pages 79–80.

Volatile liquid anaesthetics

Halothane, which was the first available drug in this class, is now not used in the UK because it produced hepatitis in patients with repeated exposures. Both sevoflurane and isoflurane also cause hepatotoxicity in those patients sensitized to halogenated anaesthetics; however, the risk is smaller than with halothane and remote with desflurane.

Steroid compounds

Cholestasis is caused by natural and synthetic oestrogens, as well as methyltestosterone. These agents interfere with canalicular biliary flow by blocking MRP2 and MDR3 (see Fig. 14.4) and cause a pure cholestasis.

Cholestasis is rare with the contraceptive pill because of the low dosage used. However, the contraceptive pill is associated with an increased incidence of gallstones, hepatic adenomas (rarely, HCCs), the Budd–Chiari syndrome and peliosis hepatis. The latter condition, which also occurs with anabolic steroids, consists of dilatation of the hepatic sinusoids to form blood-filled lakes.

Phenothiazines

Phenothiazines (e.g. chlorpromazine) can produce a cholestatic picture owing to a hypersensitivity reaction. This occurs in 1% of patients, usually within 4 weeks of starting the drug. Typically, it is associated with a fever and eosinophilia. Recovery occurs on stopping the drug.

Anti-tuberculous chemotherapy

Isoniazid produces elevated aminotransferases in 10–20% of patients. Hepatic necrosis with jaundice occurs in a smaller percentage. The hepatotoxicity of isoniazid is related to its metabolites and is dependent on acetylator status. Rifampicin produces hepatitis, usually within 3 weeks of starting the drug, particularly in patients on high doses. Pyrazinamide produces abnormal liver biochemical tests and, rarely, liver cell necrosis.

Amiodarone

This leads to a steatohepatitis histologically, and liver failure if the drug is not stopped in time.

Sodium valproate

This causes mitochondrial injury with microvesicular steatosis. Intravenous carnitine should be used as an antidote.

Drug prescribing for patients with liver disease

The metabolism of drugs is impaired in severe liver disease (with jaundice and ascites), as the removal of many drugs depends on liver blood flow and the integrity of the hepatocyte. In general, therefore, the effect of drugs is prolonged by liver disease and also by cholestasis. This is further accentuated by portosystemic shunting, which diminishes the first-pass extraction of drugs. With hypoproteinaemia, there is decreased protein binding of some drugs, and bilirubin competes with many drugs for the binding sites on serum albumin. In patients with portosystemic encephalopathy, care must be taken in prescribing drugs with a central depressant action, such as narcotics, including codeine and anxiolytics. Other common drugs to be avoided in cirrhosis include angiotensin-converting enzyme (ACE) inhibitors (which cause hepatorenal failure) and NSAIDs (which cause bleeding).

Further reading

Björnsson E. Review article: drug-induced liver injury in clinical practice. Aliment Pharmacol Ther 2010; 32:3–13.