Primary biliary cirrhosis (PBC)
This is a chronic disorder in which there is a progressive destruction of bile ducts, eventually leading to cirrhosis. It predominantly affects women aged 40-50 years (female to male ratio 6 : 1). It used to be considered rare but is now being diagnosed more frequently in its milder forms. PBe has been called ‘chronic non-suppurative destructive cholangitis’; this term is more descriptive of the early lesion and emphasizes that true cirrhosis only occurs in the later stages of the disease.
The aetiology is unknown, but immunological mechanisms may playa part. Antibodies to mitochondria (AMA) are almost invariable and of the many mitochondrial proteins, the antigen M2 is specific to PBe. There are four M2 antigen polypeptides, all components of the pyruvate dehydrogenase complex of mitochondrial enzymes. Of these E2, a 74 kDa complex of lipoamide acyltransferase, and protein X, a 52 kDa peptide, appear to be specific to PBe and an ELISA test based against these antigens has been shown to be 98% sensitive for PBe in research laboratories. However, the presence of AMA in high titre is unrelated to the clinical or histological picture and may play no part in its pathogenesis.
Although damage to bile ducts is a feature, antibodies to bile ductules are not specific to PBe. Biliary epithelium from patients with PBe expresses aberrant class II HLAs but it is not known whether this expression is the cause or result of the inflammatory response. Cell-mediated immunity is impaired (demonstrated both in vitro and by skin testing) and this suggests that sensitized T lymphocytes might be involved in producing damage. There may be a defect in immunoregulation as a decrease in T suppressor cells may allow cytotoxic T cells to produce damage to the bile ducts; there is also evidence to suggest that lymphokine secretion and cell activation is impaired in T lymphocytes at the site of tissue destruction. There is an increased synthesis of IgM thought to be due to a failure of the switch from IgM to IgG antibody synthesis.
Asymptomatic patients are discovered on routine examination or screening to have hepatomegaly, a raised serum alkaline phosphatase or autoantibodies. The earliest symptom is pruritus, often preceding jaundice by a few years. When jaundice appears, hepatomegaly is usually found.
In the later stages patients are jaundiced with severe pruritus. Pigmented xanthelasma on eyelids or other deposits of cholesterol in the creases of the hands may be seen; hepatosplenomegaly is present.
Autoimmune disorders, e.g. Sjogren’s syndrome, scleroderma, rheumatoid arthritis, occur with increased frequency. Keratoconjunctivitis sicca (dry eyes and mouth) is seen in 70% of cases. Renal tubular acidosis and membranous glomerulonephritis may occur.
MITOCHONDRIAL ANTIBODIEs-measured routinely by indirect immunofluorescence on rat kidney substrate (in titres >1 : 160)-are present in over 95% of patients. M2 antibody is specific. Other non-specific antibodies, e.g. antinuclear factor and smooth muscle, may also be present.
HIGH SERUM ALKALINE PHOSPHATASE is often the only abnormality in the liver biochemistry.
SERUM CHOLESTEROL is raised.
SERUM IGM may be very high.
ULTRASOUNO shows diffuse alteration in liver architecture and is not always necessary.
LIVER BIOPSY shows characteristic histological features of a portal tract infiltrate mainly of lymphocytes and plasma cells, sometimes with granulomas. Most of the early changes are in zone 1. There is damage to and loss of small bile ducts, leading to portal tract fibrosis and, eventually, cirrhosis. Cholestasis occurs late. Hepatic granulomas are also seen in sarcoidosis, tuberculosis, schistosomiasis, drug reactions (e.g. phenylbutazone), brucellosis, parasitic infestation (e.g. strongyloidiasis) and other conditions.
The classical picture presents little difficulty with diagnosis (high serum alkaline phosphatase and the presence of AMA); this can be confirmed by the characteristic features on liver biopsy. There is a group of patients with the histological changes of PBC, but the serology of CAH (i.e. positive antinuclear and actin antibodies but negative AMA). This has been given the name of autoimmune cholangiopathy and responds to steroids.
In the jaundiced patient, extrahepatic biliary obstruction should be excluded by ultrasound and, if there is doubt about the diagnosis, ERCP should be performed to make sure that the bile ducts are normal.
Ursodeoxycholate (10-15 mg kg'”) is of benefit in some patients with improvement in serum liver enzymes and pruritus. Azathioprine, corticosteroids and o-penicillamine have all been tried without beneficial effect, and corticosteroids are contraindicated because of bone thinning. Colchicine (0.6 mg twice daily) has been shown to improve liver function. Cyclosporin has been used in some trials with improvement in symptoms and reduced histological progression.
Malabsorption of fat-soluble vitamins (A, D and K) occurs and supplementation is required when deficiency is detected and in the jaundiced patient prophylactically. Calcium is required for osteoporosis. Hyperlipidaemia should be treated. Pruritus is difficult to control but cholestyramine, one 4 g sachet three times daily, can be helpful, although it is unpalatable. Rifampicin and naloxone hydrochloride (an opioid antagonist) have been shown to be of benefit in trials.
The lack of effective medical therapy has made PBC a major indication for orthotopic liver transplantation.
The complications are those of cirrhosis. In addition, osteoporosis, osteomalacia and a polyneuropathy can also occur.
This is very variable. Asymptomatic patients and those presenting with pruritus will survive for more than 20 years. Symptomatic patients with jaundice have a more rapidly progressive course and die of liver failure or bleeding varices in approximately 5 years. Liver transplantation should therefore be offered when the serum bilirubin reaches 100/Lmol litre:”. Transplantation has a 5 year survival of at least 70%. Secondary biliary cirrhosis Cirrhosis can result from prolonged (for months) largeduct biliary obstruction. Causes include bile duct strictures, gallstones and sclerosing cholangitis. An ultrasound examination, followed by ERCP or PTC is performed to outline the ducts and any remedial cause is dealt with.
Idiopathic haemochromatosis (IHC) is an inherited disease characterized by excess iron deposition in various organs leading to eventual fibrosis and functional organ failure.
The underlying metabolic defect is unknown, but abnormal enterocyte function resulting in inappropriate levels of iron absorption has been suggested. IHC is inherited as an autosomal recessive with only homozygotes manifesting the clinical features of the disease. It is associated with HLA-A3 (72% vs. 28% of general population); in addition HLA-B14 is increased in France and HLA-B7 in Australia. Dietary intakes of iron and chelating agents (ascorbic acid) are probably also important. Iron overload may be present in alcoholics, but alcohol excess per se does not cause IHC. There is a history of excess alcohol intake in 25% of patients. The iron accumulation is gradual and occurs throughout life.
Prevalence of homozygotes (affected) varies between 0.3 and 0.5%, with a heterozygote (carrier) frequency of 9- 14%.
In symptomatic patients the total body iron content is 20-40 g compared to 3-4 g in a normal person. The iron content is particularly increased in the liver and pancreas (50–100 times normal) but is also increased in all other organs, e.g. the endocrine glands, heart and skin. Gonadal function is impaired despite a low testicular iron content.
Histologically the liver shows extensive pigmentation and fibrosis with iron deposition in dense, fibrous septae forming a network surrounding groups of acini. Early in the disease, iron is deposited in the periportal hepatocytes (in pericanalicular lysosomes). Later it is distributed widely throughout all acinian zones, biliary duct epithelium, Kupffer cells and connective tissue. Cirrhosis is a late feature.
The course of the disease depends on a number of features including sex, dietary iron intake, presence of associated hepatotoxins (especially alcohol) and genotype. Overt clinical manifestations occur more frequently in men; the reduced incidence in women is probably explained by physiological blood loss and a smaller dietary intake of iron. Most affected individuals present in the fifth decade. The classic triad of bronze skin pigmentation (due to melanin deposition), hepatomegaly and diabetes mellitus is only present in cases of gross iron overload. Other more common features include gonadal atrophy and loss of libido.
Hypogonadism secondary to pituitary dysfunction is the commonest endocrine feature. Deficiency of other pituitary hormones is also found, but symptomatic endocrine deficiencies, e.g. loss of libido, are very rare. Cardiac manifestations, particularly heart failure and arrhythmias, are common, especially in younger patients. Calcium pyrophosphate is deposited asymmetrically in both large and small joints (chondrocalcinosis) leading to an arthropathy. The exact relationship of chondrocalcinosis to iron deposition is uncertain.
Thirty per cent of patients with cirrhosis will develop primary hepatocellular carcinoma (HCC). HCC has only rarely been described in non-cirrhotic patients in whom the excess iron stores have been removed. This has important implications for early diagnosis.