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The relationship between the thyroid gland and the liver

DOI: http://dx.doi.org/10.1093/qjmed/95.9.559 559-569 First published online: 1 September 2002


Thyroxine and tri‐iodothyronine are essential for normal organ growth, development and function. These hormones regulate the basal metabolic rate of all cells, including hepatocytes, and thereby modulate hepatic function; the liver in turn metabolizes the thyroid hormones and regulates their systemic endocrine effects. Thyroid dysfunction may perturb liver function, liver disease modulates thyroid hormone metabolism, and a variety of systemic diseases affect both organs. We highlight the intricate relations between the thyroid gland and the liver in health and disease.

Intracellular signalling

The thyroid gland secretes two iodine containing amine hormones derived from the amino acid tyrosine, L‐thyroxine (T4) and 3,5,3′‐L‐tri‐iodothyronine (T3). Free T3 and T4 enter all cells through the plasma membrane and bind to a nuclear T3 receptor. The thyroid receptor is part of the nuclear superfamily group of receptors (retinoic acid, retinoid X, vitamin D and peroxisome proliferator receptor).1 These receptors all possess six similar domains,2 two of which are a ligand‐binding region and a central region that constitutively binds to DNA.

The main function of the thyroid receptor is to act as a ligand‐activated transcription factor that regulates target gene expression directly through DNA response elements (thyroid response elements, TREs).3 However, an important property of these receptors is that they bind thyroid response elements constitutively, independent of ligand occupancy.4 The consensus sequence recognized by nuclear receptors often contains a hexamer AGGTCA known as the half site; two half‐site sequences with a specific orientation are required for efficient binding and function.5 In the central DNA‐binding region of the thyroid receptor, two zinc‐containing modules mediate the specific recognition sites (and spacing specificity) for the receptor to bind genomic DNA.6 A DNA recognition helix (P box) in the carboxy terminus of the first zinc finger mediates the half‐site sequence recognition by directly contacting the major groove nucleotides.7 Although thyroid receptors can bind to TREs as monomers, the majority bind in the form of a heterodimer with the retinoid X receptor (RXR). Heterodimer formation is thought to enhance DNA binding affinity as well as providing target gene specificity. The retinoic acid receptor (RAR), vitamin D receptor (VDR) and peroxisome proliferator receptor (PPR) also form heterodimers with the retinoid X receptor;8 however, they activate through different response elements.

Two groups of co‐factors are needed to mediate activation (co‐activators) and repression (co‐repressors) of TR transcriptional activity. Unliganded thyroid receptors are bound to co‐repressor molecules that have histone deacetylase activity. Deacetylization results in a closed chromatin configuration on genomic DNA that represses basal transcription of the target gene.9 In the presence of T3, a conformational change within the thyroid receptor allows release of the co‐repressor molecule and recruitment of a co‐activator complex.10 The SRC family and CBP proteins are thought to form part of this co‐activator complex, and these proteins have histone acetyltransferase (HAT) activity.6 Enzymic acetylization of the nucleosome allows for an open chromatin configuration of the TRE on genomic DNA. This open structure is thought to facilitate the assembly of the basal transcription machinery and increase the rate of mRNA transcription of thyroid‐responsive genes.11 This increases the intracellular expression of TRE‐related peptides, which mediate the metabolic effects of the thyroid hormones (Figure 1).12

The thyroid receptor is encoded by two separate genes TRα (chromosome 17) and TRβ (chromosome 3) in humans. Alternate splicing from each gene generates multiple isoforms, with the TRα1, TRα2 from the TRα gene and TRβ1, TRβ2 from the TRβ gene having been cloned in humans.13,,14 The TRα1 form encodes a ligand‐binding receptor, whereas the TRα2 isoform does not bind hormone, and functions to suppress expression of genes containing TREs.7 The TRβ1 and TRβ2 are both ligand‐binding receptors.7 These isoforms are distributed at various concentrations in different cells, depending on the tissue type, and individual isoforms can regulate thyroid response elements in different ways. These properties offer opportunities to develop therapeutic tools to selectively activate specific thyroid receptor isoforms.15

Figure 1.

Model for activation and repression of the thyroid hormone receptor. In the absence of T3, T3/RXR recruits a repressor complex that has histone deacetylase (HDAC) activity. Enzymic deacetylation results in a closed chromatin modification of the nucleosome that leads to transcriptional repression. In the presence of T3, TR/RXR releases the repressor molecule and recruits an activator complex that has histone acetyltransferase activity. Enzymic acetylization results in an open chromatin structure that initiates the enhancer region of the TRE and leads to promoter activation.

Thyroid hormone metabolism

In normal subjects, the thyroid gland secretes 110 nmol of thyroxine and 10 nmol of tri‐iodothyronine each day.16 Tri‐iodothyronine has a ten times greater affinity and ten times greater efficacy than thyroxine for the nuclear receptor, thus even though thyroxine is quantitatively secreted at much higher levels, it should be regarded as a pro‐hormone that requires deiodination and conversion to T3 to become biologically active.17 There are three groups of enzymes that regulate thyroid hormone metabolism, forming part of the iodothyronine seleno‐deiodinase enzyme system (type 1=D1, type 2=D2 and type 3=D3). They are responsible for the activation of T4 to T3, inactivation of T4 to rT3 and the conversion of rT3 and T3 to T2 (Figure 2).

The conversion of T4 to T3 in extrathyroidal tissue occurs through a rapidly equilibrating pool via the D1 enzyme system and a slowly equilibrating pool via the D2 system. The type 1 deiodinase is mainly found in the liver and kidney,18 and accounts for approximately 30–40% of extrathyroidal production of T3 (12 nmol). The type 2 deiodinase is found in the pituitary, the CNS, and skeletal muscle and contributes 60–70% of the extrathyroidal production of T3 (30 nmol).19 Although this enzyme system performs similar actions to the D1 group of enzymes, its kinetics, regulation and susceptibility to propylthiouracil are different.20 Although both the D1 and D2 system can also inactivate T4 and T3, the major inactivator is the type 3 deiodinase system, which primarily exhibits inner‐ring deiodination (unlike the other systems).21 It is found in the liver, skin and CNS, where it catalyses the conversion of T4 to rT3 and T3 to T2, both inactive metabolites; it also converts rT3 to rT2.20 This enzyme system is also expressed in placenta, where it protects the foetus from maternal thyroid hormones.22

In addition to the central role in deiodination to activate and deactivate thyroid hormones, the liver performs specific functions relating to thyroid hormone transport and metabolism.

The liver extracts 5–10% of plasma T4 during a single passage, as shown by studies using [131I]T4. This value is much higher than can be accounted for by the amount of free T4 delivered to the liver, indicating that a substantial amount of protein‐bound T4 is available for uptake.23 An active stereospecific transport mechanism has been identified for transporting T4 and T3 across the hepatocyte membrane. The intracellular concentrations of the free hormone are higher than the plasma levels, and the process is energy‐dependent.24

The liver synthesizes a number of plasma proteins that bind the lipophilic thyroid hormones and thereby provide a large, rapidly exchangeable pool of circulating hormone. The thyroid hormones are >99% bound to thyroxine‐binding globulin, thyroxine‐binding prealbumin and albumin in plasma. The free hormone component within plasma is in equilibrium with the protein‐bound hormone, and it is this free fraction which accounts for the hormone's biological activities. The plasma concentrations of free T4 and T3 are at a steady concentration, so that the tissues are exposed to the same concentrations of the free hormone. However, the free hormone concentrations in different tissues vary according to the transport and deiodinase activity within specific tissues.20

Thus tissue thyroid status depends not only on thyroxine secretion but also on normal thyroid hormone metabolism, delivery of T3 to nuclear receptors and on receptor distribution and function. Normal thyroid function, which is essential for normal growth, development and the regulation of energy metabolism within cells, is dependent on a normally functioning thyroid and liver axis.

Figure 2.

Structures and interactions between the principal iodothyronines.

Thyroid metabolism in chronic illness

In most chronic illness, defects arise in thyroid hormone metabolism, resulting in the sick euthyroid syndrome. This is characterized by a normal total T4, normal/high free T4, low total T3, low free T3 and an elevated rT3. These changes reflect a reduction in D1 activity, an increase in D3 activity20 and changes in the plasma concentration of thyroid‐binding proteins and free fatty acids (which displace thyroid hormones from binding proteins). There are also non‐thyroidal influences on the hypothalamic‐pituitary‐thyroid axis, e.g. cortisol inhibiting TSH secretion.25

It has been suggested that this syndrome may confer a survival advantage, which adapts an organism to chronic illness by reducing the basal metabolic rate within cells and thereby reducing caloric requirements.

Thyroid abnormalities in liver disease

In the different types of liver disease, similar processes may occur to those seen in the sick euthyroid syndrome, but in addition a number of changes specific to the type or stage of liver disease are also found.


A prospective study in 118 patients with cirrhosis demonstrated a 17% increase in thyroid glandular volume, assessed by ultrasonography, as compared to controls.26 The most consistent thyroid hormone profile in patients with cirrhosis are a low total and free T327 and an elevated rT3,28 similar changes to those in the sick euthyroid syndrome, probably reflecting a reduced deiodinase type 1 activity, resulting in reduced conversion of T4 to T3. This results in an increase in conversion of T4 to rT3 by the deiodanase type 3 system, and an increase in the rT3 to T3 ratio. The plasma T3:rT3 ratio has a negative correlation with the severity of cirrhosis when assessed in non‐alcoholic cirrhotics.29 Since T3 and rT3 bind to the same plasma proteins, the T3/rT3 ratio provides a parameter of liver function that is largely independent of protein binding. Both the T3/rT3 ratio and free T3 levels in plasma thus provide a correlate of liver function in cirrhosis, and are of prognostic value, albeit seldom used.30

The low total and free T3 levels may be regarded as an adaptive hypothyroid state that serves to reduce the basal metabolic rate within hepatocytes and preserve liver function and total body protein stores. Indeed, a recent study in cirrhotic patients showed that the onset of hypothyroidism from intrinsic thyroid disease of various aetiologies during cirrhosis resulted in a biochemical improvement in liver function (e.g. coagulation profiles) as compared to cirrhotic controls.31 Hypothyroidism has also been associated with lesser degrees of decompensation in cirrhosis.32 Controlled induction of hypothyroidism might therefore be beneficial in cirrhotic patients, but further studies are required to test this hypothesis.

Acute hepatitis and acute liver failure

In acute hepatitis of mild or moderate severity, patients have elevated serum levels of total T4, due to increased thyroid‐binding globulin, which is synthesized as an acute‐phase reactant, but normal levels of free T4. In more severe cases with impending liver failure, the data is variable, and low total T4 levels may reflect reduced hepatocellular synthesis of thyroid‐binding globulin.33 Serum T3 levels are extremely variable, but the free T3:T4 ratio correlates negatively with the severity of the liver disease and has prognostic value.33 Again this probably reflects diminished type 1 deiodinase activity, resulting in a reduced conversion of T4 to T3; in general, however, these patients are clinically euthyroid. Some series have described patients with acute hepatic failure (especially viral hepatitis) as having goitres that resolved with improvement in liver function.34

Specific forms of chronic liver disease

In patients with chronic hepatitis associated with primary biliary cirrhosis (PBC) or chronic autoimmune hepatitis, there is an increased prevalence of autoimmune thyroid disease.35,,36 Thus abnormalities may arise from thyroid gland dysfunction or as a consequence of the liver disease. Autoimmune hypothyroidism is a prominent feature in PBC, occurring in 10–25% of patients.37 There is often an increase in total T4 in PBC, due to an increase in thyroid‐binding globulin levels, and this may mask hypothyroidism, emphasizing the need to perform a free T4 and TSH assay. Anti‐thyroid microsomal antibodies are common in PBC (34%), as are anti‐thyroglobulin antibodies (20%).38 Thyroid dysfunction may precede or follow the diagnosis of PBC. In autoimmune hepatitis, both Grave's disease (6%) and autoimmune hypothyroidism (12%) are relatively common.36 Primary sclerosing cholangitis is associated with an increased incidence of Hashimoto's thyroiditis, Graves's disease and Riedel's thyroiditis.39

In patients with chronic hepatitis who do not have co‐existing autoimmune liver and thyroid disease, total T4, total T3, thyroxine‐binding globulin levels are often increased, but TSH and free T4 levels are usually normal, and patients are clinically euthyroid.40

Currently the treatment of viral hepatitis with alpha interferon has added another dimension to the abnormalities of thyroid function seen in chronic liver diseases. In different studies assessing patients treated with alpha interferon for hepatitis C, 2.5–10% developed thyroid dysfunction,41,,42 with both thyrotoxicosis (due to acute thyroiditis) and hypothyoidism being observed. Although the reason is not altogether clear, the induction of an autoimmune reaction has been postulated, resulting in the development of anti‐thyroid and anti‐thyrotrophin receptor antibodies.43 However, a distinct effect on intrathyroidal organification of iodine has also been suggested.44 The risk factors for developing thyroid dysfunction with alpha interferon (which may persist after discontinuation of the drug) are female sex, underlying malignancy, high doses of long duration, combination immunotherapy (especially Il‐2), and the presence of anti‐thyroid peroxidase antibodies prior to commencing treatment.45–,47 It should be noted that interferon therapy causes weakness and muscle aching, and in this setting the myopathy of hypothyroidism may be missed. It is therefore recommended that thyroid function tests (including thyroid antibodies) are performed prior to therapy, and subsequently monitored at 3–6 month intervals during interferon therapy.48

In chronic hepatitis B, predominantly a disease of males, the frequency of pre‐treatment thyroid antibodies and the induction of thyroid antibodies and thyroid dysfunction during interferon therapy, are all lower than in chronic hepatitis C.49

Overall, the majority of patients with liver disease are clinically euthyroid, and this can be confirmed with a normal high sensitivity TSH test and a normal free T4. The latter test is routinely performed and obviates the need to take into account the variation in thyroid‐binding globulin levels seen in patients with liver disease.

Liver abnormalities in thyroid disease


Hypothyroidism may have features that mimic liver disease (pseudo‐liver disease): examples include myalgias, fatigue and muscle cramps in the presence of an elevated aspartate aminotransferase from a myopathy,50 coma associated with hyperammonaemia in myxoedema coma,51 and myxoedema ascites.52 Myxoedema ascites, generally a high protein content ascites suggestive of an exudate, has been varyingly interpreted as an intrinsic liver defect or a phenomenon mimicking liver disease. It had been proposed that the ascites was a consequence of chronic right‐sided heart failure, resulting in central scarring of the liver.53 The liver biopsy findings of central congestive fibrosis in a number of patients would support this.52 However, another study reported normal right heart pressures, and proposed that severe hypothyroidism caused enhanced permeability of vascular endothelium, resulting in ascites and serous effusions throughout the body.54 Following initiation of thyroid replacement therapy, myxoedema ascites resolves over a few months.

There is also evidence that hypothyroidism may directly affect the liver structure or function. Hypothyroidism has been associated in a few case reports with cholestatic jaundice attributed to reduced bilirubin and bile excretion. In experimental hypothyroidism, the activity of bilirubin UDP‐glucuronyltransferase is decreased, resulting in a reduction in bilirubin excretion.55 The reduction in bile flow may be in part due to an increase in membrane cholesterol‐phospholipid ratio and diminished membrane fluidity,55 which may affect a number of canalicular membrane transporters and enzymes, including the Na+, K+‐ATPase. The triad of reduced bilirubin excretion, hypercholesterolaemia and hypotonia of the gall bladder seen in hypothyroidism increases the incidence of gallstones.56 Recent studies have shown that the hepatic abnormalities associated with hypothyroidism can be reversible over a matter of weeks with thyroxine replacement, with no residual liver damage.57,,58

In rats, hypothyroidism may protect against acetaminophen toxicity and diminish thioacetamide toxicity, but there is no evidence for this in man.59,,60


The clinical features of hyperthyroidism are diverse, involving nearly every system in the body. Liver injury caused by thyrotoxicosis is relatively common, and can be conveniently divided into hepatitic or cholestatic types.

Hepatitic injury

An increase in the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) was reported in 27% and 37% of patients respectively,61 although the majority of these patients showed no other clinical or biochemical features of liver impairment. The mechanism of injury appears to be relative hypoxia in the perivenular regions, due to an increase in hepatic oxygen demand without an appropriate increase in hepatic blood flow. In mild cases, liver histology shows non‐specific changes, which on light microscopy consist of a mild lobular inflammatory infiltrate consisting of polymorphic neutrophils, eosinophils and lymphocytes, associated with nuclear changes and Kupffer cell hyperplasia. Electron microscopy may reveal hyperplasia of the smooth endoplasmic reticulum, a paucity of cytoplasmic glycogen and increased number and size of mitochondria, which may contain more cristae.57 A small proportion of patients have a progressive liver injury, which histologically consists of centrizonal necrosis (Figure 3) and perivenular fibrosis, affecting the areas in which hypoxia may be most prevalent. The severity of centrizonal necrosis can be assessed using plasma isocitrate dehydrogenase levels in plasma, offering a convenient method for grading the hepatic injury.62 The clinical presentation of this type of injury is usually that of a self‐limiting hepatitis; however, there are a few case reports of thyrotoxic patients presenting with fulminant hepatic failure.63 The precipitation of the clinical presentation is generally attributable to the onset of cardiac failure, often precipitated by arrhythmias.63

Figure 3.

H&E‐stained section of centrizonal necrosis secondary to thyrotoxic liver injury. Hv, hepatic vein; Cn, centrizonal necrosis in zone 3 of the hepatic lobule.

Cholestatic injury

An elevated serum alkaline phosphatase is seen in 64% of patients with thyrotoxicosis.64 However this is not necessarily liver‐specific, as it can originate from bone and/or liver. It is therefore important to look at elevations in γ‐glutamyl transpeptidase (17%) and bilirubin (5%) as an indicator of cholestasis.64 In patients with cholestatic injury, the histological features are similar to the non‐specific changes seen in hepatitic injury. However, in addition there appears to be centri‐lobular intrahepatocytic cholestasis (Figure 4).65 Jaundice is uncommon but when it occurs, complications of thyrotoxicosis (cardiac failure/sepsis) or intrinsic liver disease need to be excluded.

It is difficult to establish which features seen in thyrotoxic liver injury are from tissue thyroid status alone, and which are in combination with complications such as cardiac failure, malnutrition and sepsis. It is probably impractical to try and separate the causes out, as awareness of the presentation, complications and treatment are of greater importance. The early reports of patients developing a spectrum of pathological changes from focal necrosis with fatty change to cirrhosis can be attributed to untreated hyperthyroidism.65 Modern therapies have made chronic liver disease a very rare complication of hyperthyroidism.66 In the vast majority of cases, the hepatic abnormalities associated with hyperthyroidism are reversible, following the early recognition and treatment of the disorder.66

However, therapy may itself cause hepatic complications. Increased serum levels of aspartate aminotransferase and alanine aminotransferase occur in about 30% of patients treated with propylthiouracil.67 The rise in AST appears to be dose‐related, so that AST and ALT levels are highest during the first few weeks of treatment, falling rapidly with a dose reduction.68 In the majority of patients, serum aminotransferases return to normal, with clinical improvement following withdrawal of treatment. Rarely, a persistent hepatitis occurs with clinical, biochemical (elevated bilirubin, AST and ALT) and histological features of hepatocellular necrosis.69 This is an idiosyncratic reaction that can develop at any time, but usually occurs within the first 2 to 3 months of treatment in about 1% of patients, usually women aged <30 years. It is considered to be an allergic host response, which generally resolves over a protracted period of time.70 A small proportion of patients develop fulminant hepatic failure, and in the presence of severe acidosis or a combination of grade III/IV encephalopathy, renal failure and coagulopathy, may require orthotopic liver transplantation.69,,71 Abnormalities of liver function are much less common with carbimazole and methimazole. These agents induce cholestasis, as an idiosyncratic reaction to the drug.72 An elevation of the bilirubin, alkaline phosphatase, and γ‐glutamyl transpeptidase levels are the predominant abnormalities. Such liver dysfunction usually presents within 2–3 weeks of initiation of treatment, and can persist for several months despite discontinuation of the offending drug.73 The predominant feature on liver biopsy is intrahepatic cholestasis.

Hepatic injury can occasionally develop over the first few months in patients starting anti‐thyroid therapy. Predicting the incidence in individual patients is difficult, and it is therefore recommended that liver function tests are performed in all patients within 3 months of commencing therapy.68

Figure 4.

Electron micrograph of intrahepatocytic cholestasis. Ch, cholestasis (black pigment); N, nucleus; M, mitochondria.

Other thyroid and liver interactions


The liver is the major site for cholesterol and triglyceride metabolism, and the thyroid hormones play an integral part in hepatic lipid homeostasis. Thyroid hormones increase the expression of LDL receptors on the hepatocytes,74 and increase the activity of lipid‐lowering liver enzymes, resulting in a reduction in low‐density lipoprotein levels.75 Thyroid hormones also increase the expression of apolipoprotein A1, a major component of high‐density lipoprotein.76 Clearly, the above effects of the thyroid hormones could be beneficial in reducing the onset of atherosclerosis if they were elicited without the deleterious effects, particularly cardiac effects such as atrial arrhythmias.77,,78 A series of 3,5‐diodo‐3‐aryl‐substituted thyronines have been developed, which show a potent cholesterol‐reducing effect in hypercholesterolaemic rats, without producing tachycardia. The tissue selectivity of these agents was attributed to selective uptake by the liver rather than TR subtype selectivity.79 Subsequently, a series of novel thyronine type derivatives (dimethyl‐isopropyl‐benzylphenoxy‐acetic acid) (GC‐1) have reduced serum cholesterol in rats, without tachycardia, by selective activation of the TRβ isoform.15 This is compatible with the predominant distribution of the TRβ isoform in the liver and the TRα isoform in the cardiovascular system.


A number of disease processes can affect both the liver and the thyroid gland simultaneously. The autoimmune diseases, which may occasionally occur in the setting of a multisystem autoimmune disorder, have been discussed.80

A less common setting in which generalized pathology occurs is that of organ infiltration such as malignancy, amyloid, or in secondary haemachromatosis, when iron is diffusely deposited. Of the infiltrating malignancies, non‐Hodgkin's lymphoma is the commonest cause, and the presentation is usually dominated by a goitre (with or without lymphadenopathy), jaundice and a paraneoplastic illness.81 Occasionally, other forms of hepatic impairment (e.g. coagulopathy) and hypothyroidism can occur as part of the presentation.82 Secondary amyloidosis due to systemic inflammatory diseases (e.g. Crohn's, tuberculosis, familial Mediterranean fever) is the commonest cause of amyloid deposition into the liver and thyroid gland,83 characterized by the deposition of the serum amyloid A (AA) protein.84 The synthetic function of each organ is usually well maintained, thus amyloid organ function is better followed by serial measurement of serum amyloid A protein and amyloid P scintigraphy.85 Aggressive treatment of the underlying inflammatory disorder to maintain serum amyloid A values within the reference range (<10 mg/l) is associated with a 50% reduction in mortality at 10 years.86 Transfusion‐related iron deposition (secondary haemochromatosis) can rarely cause multiple endocrine abnormalities (including hypothyroidism) and cirrhosis from iron deposition into the respective organ.87,,88 The toxicity of the iron deposition into the thyroid (and thus degree of hypothyroidism) is potentiated by hypoxia and anaemia, making these patients difficult to treat.89

Amiodarone is the most notable drug that effects both the liver (fibrosis) and the thyroid gland (hypo/hyperthyroidism),90 and its effects may remain even following drug withdrawal. The antimalarial drug mefloquine can cause a self‐limiting hepatitis and thyrotoxicosis from acute thyroiditis, but the symptoms appear to resolve when the drug is withdrawn.91 Another major drug class affecting both organs is the anti‐epileptics, of which carbamazepine can cause hepatic impairment and subclinical hypothyroidism from abnormal thyroid hormone metabolism.92 Finally, the treatment of malignant disease using radical radiotherapy regimes, including those containing 131I MIBG and modern chemotherapy schedules, have been associated with a greater degree of toxicity effecting both organs.93

Recent work investigating the use of tri‐iodothyronine as a hepatic growth factor has shown it to be a primary mitogen for the liver in animal models (i.e. it induces hepatocyte proliferation and increases liver mass when administered at high doses in the absence of hepatic injury).94 The ability to increase liver mass in the absence of liver damage, and to enhance proliferation during compensatory hyperplasia after liver damage, could be therapeutically valuable if applicable to man. More generally, the ability to manipulate liver cell proliferation in vivo may be helpful in designing cell transplantation95 and gene therapy approaches to liver diseases.96


A complex relationship exists between the thyroid gland and the liver in both health and disease. A multisystem approach to treating patients with diseases affecting either organ is vital to avoid missing subtle but clinically relevant abnormalities.


  • Address correspondence to Dr R. Malik, MRC Training Fellow, Centre for Hepatology, Department of Medicine, Royal Free Campus, Royal Free and University College Medical School, Rowland Hill Street, Hampstead, London NW3 2PF. e‐mail: r.malik{at}rfc.ucl.ac.uk


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