Liver in Systemic Disease

Bariatric surgery

Bariatric surgery to treat severe obesity includes restrictive and malabsorptive procedures, some of which may be combined. Roux-en Y gastric bypass is a common restrictive and malabsorptive procedure. Nutritional complications include protein malnutrition (‘secondary kwashiorkor’) and a variety of micronutrient deficiencies. A study of the effects of bariatric surgery on liver injury with biopsy at 1 and 5 years showed reduced steatosis and ballooning that correlated with improved insulin resistance, and a slight increase in postoperative hepatic fibrosis at 5 years, although early stage in 95% of patients. Liver failure has occurred in obese patients after jejuno-ileal bypass, a procedure that is no longer performed.

Intestinal failure-associated hepatic disease in young infants

IFALD-associated cholestasis in neonates is more likely with longer treatment, with younger gestational age and low birth weight. The differentials include ‘physiological’ cholestasis, sepsis and the numerous other causes of neonatal cholestasis (see Chapter 3 ). Morphologically, the individual changes are not specific and extremely variable. ^, Bilirubinostasis is consistently present and may develop in a matter of days; cholestatic rosettes are often present; bile plugs may also be present in interlobular bile ducts. Steatosis is infrequent. Hepatocellular ballooning is more often severe than in older children or adults. The portal tracts show a variable mixed inflammatory cell infiltrate and, with prolonged therapy, a periportal ductular reaction; progressive fibrosis can produce biliary cirrhosis ( Fig. 15.8 ). During prolonged treatment, serial liver biopsy may be needed to assess fibrosis, which is common but not usefully predicted or monitored by serum liver function tests ^{, ,} ; fibrous progression varies widely between individuals. ^,

The pathogenesis of IFALD-associated cholestasis is uncertain. Suggestions have included altered bile composition with (in neonates) immature hepatic bile acid metabolism and transport, the lack of enteral nutrition with disturbed enterohepatic circulation of bile acids, suppression of trophic or secretion-stimulating hormones and the composition of the infusate (including nutritional deficiencies or direct epithelial toxicity). ^,

Intestinal failure-associated hepatic disease in older children and adults

Hepatic abnormalities are common in older children and adults with IFALD, in particular bilirubinostasis and periportal steatosis, but the incidence is difficult to establish and, in most cases, biochemical evidence of dysfunction is transient. High-calorie dextrose-based PN has been superseded by lower calorie infusions containing lipid emulsions, with a reduced incidence of hepatic dysfunction. Increases in serum bilirubin are milder and less common than in infants, but increased serum transaminases, alkaline phosphatase and γ-glutamyltranspeptidase affect 20–60% of patients, may develop after 5–20 days of treatment and persist in 15–25% of patients who receive long-term PN. ^, Perivenular bilirubinostasis develops after 2–3 weeks on PN and may be accompanied by periportal inflammation and portal fibrosis that persists after stopping PN ( Fig. 15.9 ). ^{, ,} Chronic cholestasis in IFALD-associated liver disease is associated with significant secondary copper overload. The steatosis may reflect unbalanced lipid turnover; carnitine and choline deficiency have each been postulated. ^, Buchman and colleagues emphasized the pathologic differences between IFALD-associated steatosis and that of nonalcoholic fatty liver disease (NAFLD), with the former distinguished by its periportal distribution, often admixed microvesicular steatosis, rarity of steatohepatitis, together with the concurrence of bilirubinostasis and portal biliary features (oedema, ductular reaction, ductopenia), and a ‘jigsaw’ pattern of fibrosis versus perisinusoidal fibrosis. If conservative management of IFALD-related liver disease fails, isolated intestinal or intestine/liver transplantation may be indicated.

Primary sclerosing cholangitis

The majority (∼80%) of patients with PSC also have IBD at some point in their life, often preceding diagnosis of PSC. The development of PSC in IBD is thought to reflect common susceptibilities to the development of unbalanced mucosal immune responses to environmental stimuli. PSC is more prevalent in patients with UC (1–5%) than with Crohn disease (1–3%) (see Chapter 9 ) but the colitis associated with PSC often has a relatively distinct phenotype (pancolonic or predominantly right sided, but relatively quiescent with increased incidence of colonic dysplasia). PSC patients have an estimated 150-fold increased risk of cholangiocarcinoma, which affected 13% patients in one large follow-up study, was commonly apparent at or soon after diagnosis of PSC, with a subsequent incidence of ∼1.5% per year, the risk being confined to those PSC patients with IBD. ^, A detectable gallbladder mass in patients with PSC is sufficiently likely to be carcinoma to merit cholecystectomy. Small duct PSC, in which the cholangiogram is normal, is relatively uncommon but requires liver biopsy for diagnosis and is typically associated with IBD; some patients progress to manifest large-duct PSC. Approximately 70% of children with PSC have IBD, usually UC or, less often, colonic Crohn disease, the liver disease preceding, coinciding or following IBD. The term ‘autoimmune sclerosing cholangitis’ (ASC) in children refers to the presence of cholangiopathy (as detected by cholangiography) in patients with serological and histological features of autoimmune liver disease (see Chapter 9 ). IBD is present in approximately 40–50% of patients with ASC, as opposed to ∼20% of children with typical autoimmune hepatitis.

Steatosis

Macrovesicular steatosis is the commonest histological liver abnormality in IBD, affecting 25–40% of patients. While steatosis may be directly related to IBD-associated inflammation and dysbiosis, concurrent metabolic syndrome is also an important contributor. Indeed, steatosis can persist after colectomy. Hepatomegaly is unusual.

Chronic hepatitis

A diagnosis of chronic hepatitis should not be made unless cholangiography is normal: historical reported prevalence rates up to 10% were likely overestimates due to the difficulties in discriminating autoimmune hepatitis from PSC and an inability to account for post-transfusional chronic hepatitis C viral infection. An estimate of 1–2% seems likely for UC, but there is little evidence of an association with Crohn disease.

Cirrhosis

Edwards and Truelove reported that cirrhosis was present in 2.5% of patients with UC and accounted for 10% of deaths over 20 years follow-up. The overall prevalence of cirrhosis is about 2–5%, ^{, ,} about 12–50-fold more common than controls without chronic IBD. Patients with extensive colonic disease are most at risk. Cirrhosis may develop as a sequel to PSC where it will show a biliary pattern, or less commonly due to chronic hepatitis (viral or auto­­immune). Cirrhotic patients with colectomy may suffer variceal bleeding at the ileostomy stoma or ileo-rectal anastomosis. ^, Colonic disease may be exacerbated after liver transplantation for PSC.

Cholangiocarcinoma

Approximately 8–20% of patients with cholangiocarcinoma of the proximal bile ducts have UC, and such patients are on average 20 years younger than those without IBD. ^, The risk of cholangiocarcinoma is increased 10–30-fold in patients with UC, but in Crohn disease the association appears to be uncommon. The carcinoma develops as a complication of PSC, which is considered a premalignant condition from which carcinoma develops in 10–15% of cases. Biliary intraepithelial neoplasia (BilIN) can be seen adjacent to invasive cholangiocarcinoma ( Fig. 15.10 ). Carcinoma usually develops in patients with longstanding (≥15 years), extensive and severe UC, occasionally some years after total colectomy. ^, Radiological discrimination from duct involvement by PSC is challenging and cholangiocarcinoma may not be diagnosed until liver resection at transplantation or at autopsy. The prognosis is dismal, with a mean survival time of approximately 6–18 months. Liver transplantation is of limited value and carcinoma diagnosed incidentally at the time of operation may recur in the allograft.

Other changes

Patients with Crohn disease have a 2-fold increased incidence of gallstones but this increases to 5–10-fold with disease of the terminal ileum, related to the extent and duration of the ileal disease or ileal resection. This complication is thought to be due to bile acid malabsorption and possibly changes in bile acid composition, causing cholesterol saturation in the bile. The gallbladder itself can be affected by Crohn disease.

Amyloidosis AA affects about 0.5% IBD patients. ^, It is more common in Crohn disease than UC and merits consideration in Crohn disease patients presenting with hepatomegaly. Regression of amyloidosis has been reported after colectomy.

Hepatic granulomas are found in approximately 5% of IBD patients, predominantly in Crohn disease, ^, and may resolve soon after colectomy. Granulomas may also be associated with drug hepatotoxicity related to treatment of IBD, including TNF-α antagonists and sulfasalazine or mesalazine. Approximately 3% of patients with granulomatous hepatitis have Crohn disease.

Pylephlebitis and pyogenic abscess are rare complications of IBD, although can be the presenting feature, encountered mainly in Crohn disease. Abscesses are often multiple, in the right lobe, yield a positive culture and there is often bacteraemia. Unusual differentials such as amoebic liver abscess due to unrecognized amoebic colitis merit consideration, particularly if a patient is on immunosuppressive anticolitic therapy. Another differential diagnosis is of so-called aseptic abscesses, an apparently noninfectious condition that predominantly presents in patients with IBD. Typically, there are lesions in multiple organs including usually the spleen and lymph nodes (unlike infective abscess), the liver (40% of patients) and less frequently other organs. Microscopically, there is granulomatous inflammation surrounding abundant central neutrophil infiltration. The condition usually responds to corticosteroids, although may relapse. Inflammatory pseudotumour has also been reported in isolated patients with Crohn disease.

Patients with IBD have an overall threefold increased risk of venous thromboembolism, but this is much greater during disease flares, although an unique cause has not been found. Portal vein thrombosis occurs in both UC and Crohn disease ; it is rare overall but is common after abdominal surgery: thrombosis affecting main or segmental branches of the portal vein affects about 40% of patients undergoing proctocolectomy, usually nonocclusive in the more proximal branches. ^, There is a reported association with postoperative pouchitis. Mesenteric thrombosis and Budd–Chiari syndrome due to hepatic vein thrombosis are rare complications in IBD. Nodular regenerative hyperplasia was present in 6% of thiopurine-naïve IBD patients.

PN is often used in severe Crohn disease (see earlier discussion and Fig. 15.8 ). Many of the therapeutic agents used in the treatment of IBD also have hepatotoxicity (see Chapter 12 ), including thiopurines (such as azathioprine), aminosalicylates (sulfasalazine or mesalazine), TNF inhibitors (infliximab or adalimumab), methotrexate and corticosteroids. There is a possible association of hepatosplenic T-cell lymphoma in young patients with IBD receiving TNF-α inhibitor or thiopurine therapy. Immunosuppressive treatment of IBD can cause reactivation of chronic viral hepatitis, in particular hepatitis B. ^, Liver dysfunction may occur as part of multiorgan failure when there is toxic megacolon.

Hepatic angiomyolipoma has been described in a patient with UC.

Coeliac disease

Coeliac disease can affect individuals of any age and affect any organ, with extraintestinal symptoms recognized to be more prevalent in the clinical presentation. About 20–40% of coeliac disease patients have abnormal serum transaminases (and less often raised alkaline phosphatase) at diagnosis. Conversely, coeliac disease is a potential cause for raised transaminases of unidentified cause or is an unsuspected comorbidity revealed, for example, during treatment for hepatitis C. The raised transaminases normalize in many patients within a year on a gluten-free diet; in such individuals they are thought to be secondary to the intestinal mucosal injury and altered permeability of coeliac disease, associated with altered microbiota and microbial products draining to liver. ^, Changes on biopsy include steatosis and nonspecific reactive hepatitis. ^, However, coeliac disease also confers a 4–10-fold increased risk of specific autoimmune liver disease, before or after coeliac diagnosis, ^, most often PBC (about 6%), ^{, ,} followed by autoimmune hepatitis, then PSC. ^, These conditions are not improved on a gluten-free diet and there is an increased risk of liver fibrosis or cirrhosis (meriting consideration of coeliac disease as a comorbidity in the differential diagnosis of cryptogenic cirrhosis) ^, and liver failure. Nodular regenerative hyperplasia and biopsy-proven noncirrhotic portal hypertension is also reported. Rarely, hepatic T-cell lymphoma may occur.

Whipple disease

Whipple disease ( Tropheryma whipplei infection) often shows nonintestinal involvement, which may be the only manifestation of the disease. Inappropriate immunosuppressive therapy, for example of undiagnosed T. whipplei arthropathy with TNF inhibitors, can trigger severe localized or disseminated forms of T. whipplei , including sepsis. Infected PAS-positive-diastase-resistant foamy macrophages which characterize the intestinal involvement may also be found in the liver ( Fig. 15.11 ). ^, The ‘sickle-form’ bacilli seen in these macrophages have been described in Kupffer cells. Noncaseating epithelioid granulomas also occur in the liver in Whipple disease and may precede the onset of intestinal symptoms ; these granulomas, however, do not contain identifiable bacilli. PCR for T. whipplei is useful to demonstrate the presence of organisms. Massive steatosis has been described in one patient.

Eosinophilic gastroenteritis

Hepatic granulomas with a prominent eosinophil infiltrate have been reported in two patients, while two case reports document mild and intense eosinophil infiltration of portal tracts. ^, Sclerosing cholangitis has been described in the hypereosinophilic syndrome in which there was intestinal involvement. ^,

Diabetes mellitus

The role of type II diabetes in the development of NAFLD is discussed in Chapter 5 . Here we consider the liver abnormalities in insulin-dependent type I diabetes. The liver is central to carbohydrate and lipid metabolism. Insulin deficiency shifts hepatic metabolism towards gluconeogenesis, increasing glucose release from the liver. Declining glucokinase levels (insulin-regulated) also become rate limiting and limit hepatic trapping of glucose from sinusoidal blood. Together with reduced peripheral tissue uptake of glucose, these changes cause hyperglycaemia. Conversely, in diabetics on insulin, glycogen can accumulate within the cytoplasm and nuclei of hepatocytes. The cytoplasmic glycogen appears ultrastructurally predominantly as rosetted composites of particles (alpha granules), nuclear glycogen as smaller dispersed particles. Nuclear glycogenation is seen more often in periportal than perivenular hepatocytes and is very nonspecific but considered to correlate closer with diabetes than obesity. ^, Abnormal hepatic glycogen loading has been attributed to high insulin dosing in hyperglycaemia, which promotes glycogen storage that can accumulate with time or sometimes very acutely: typical clinical scenarios include vigorous treatment of acutely presenting diabetes with high-dose insulin ^, ; also long-term poor diabetic control involving repeated excessive insulin dosing that is then self-corrected with high quantity glucose intake; or chronic hyperglycaemia with intermittent insulin dosing. Consequent hepatomegaly due to glycogen loading of the liver in type I diabetics on insulin was described by Mauriac in 1930 as part of a childhood syndrome characterized by poor glycaemic control, growth retardation, pubertal delay and cushingoid features. However, such acquired glycogenosis can also affect adults with type I diabetes. ^{, ,} The characteristic presentation is with hepatomegaly that may be painful and with raised serum transaminases (sometimes dramatically so) in a context of poor diabetic control. The changes resolve with improved glycaemic control and are not thought to lead to chronic liver injury. ^{, , ,} The liver histology of 14 affected adults and children was reviewed in detail, for which the term ‘glycogenic hepatopathy’ was coined and has subsequently become prevalent to describe the condition ( Fig. 15.12A ). Hepatocytes are enlarged, with rarefied, pale staining cytoplasm replete with glycogen (demonstrable with PAS), frequent nuclear glycogenation, giant mitochondria and prominent cell borders contrasting with the pale cytoplasm. Sinusoids appear compressed. Steatosis was absent or sparse in most cases, and fibrosis mild in two only, one showing mild steatohepatitis with mild fibrosis. Rebiopsy in one patient after adequate glycaemic control and resolution of signs showed normal liver. A recent series of 31 diabetic children (19 with liver biopsy) showed similar histological features of glycogenosis, but more prevalent steatosis, inflammation and fibrosis. Acquired metabolic glycogenosis can occur without type 1 diabetes, in the setting of metabolic syndrome with reduced glucose tolerance or sugar-rich diet such as from sugar-rich drinks. Adipokines related to metaflammation impair skeletal muscle uptake of glucose, normally the route for most insulin-stimulated glucose disposal. High endogenous insulin levels in such a setting of peripheral insulin resistance would favour hepatic glycogenosis. The glycogenosis may be focal but in some cases is diffuse and striking ( Fig. 15.12B–D ). A recent study documented frequent occurrence in biopsies with NAFLD, both from children and adults, associated with milder degrees of fibrosis and steatosis.

The altered lipid metabolism in type 1 diabetes includes the mobilization of free fatty acids from adipose to be converted to triglyceride and very-low-density lipoprotein (VLDL) in liver, where they accumulate. Decreased lipoprotein lipase (insulin-regulated) perpetuates this hyperlipidaemic accumulation of triglyceride and VLDL. Hepatocellular fatty acid oxidation can generate acetyl coenzyme A (CoA) sufficient to saturate the oxidative enzymes and cause ketone formation. However, type 1 diabetes is not itself associated with significant hepatic steatosis, unlike type II diabetes, confirmed with magnetic resonance imaging in a large comparative study and in a biopsy-based survey of 155 children with steatosis on liver biopsy.

Collagenization of the space of Disse, together with deposition of basement membrane components, has been reported in diabetes mellitus ^, (latterly termed ‘diabetic hepatosclerosis’ when present without steatosis) and thought to represent liver involvement as part of diabetic microangiopathy. ^, An association with cholestasis has also been suggested. However, no specific association with perisinusoidal fibrosis was found in a cross-sectional comparative study of liver biopsies from 89 diabetics (half insulin-dependent) and matched controls. Instead, the authors identified hepatic arteriolosclerosis as significantly increased in hypertensive diabetics and raised again a possible association with cholestatic liver biochemistry and biliary abnormalities.

Iron-induced beta cell injury was initially proposed as the cause of diabetes in haemochromatosis, although insulin resistance appears also to be involved. The reciprocal influence of iron and insulin and the relationship between steatohepatitis, diabetes and iron overload are complex and discussed further in Chapter 4 . There is an association between type I diabetes and autoimmune hepatitis. ^,

Diabetics are at increased risk of liver neoplasms. Subjects with an inherited monoallelic mutation of the transcription factor 1 (TCF1) gene encoding for the hepatocyte nuclear factor 1α (HNF1α) may develop maturity-onset diabetes of the young type 3 and liver adenomatosis when the second allele is inactivated in hepatocytes (see Chapter 13 ). ^, There are case reports of nodular regenerative hyperplasia, of xanthomatous neuropathy affecting unmyelinated nerve fibres in the hilum and in large portal tracts, of intrahepatic and perihepatic abscess and of PSC occurring in patients with diabetes. Liver injury attributable to drugs used in the treatment of diabetes is described in Chapter 12 .

Hyperthyroidism

Abnormal liver function tests are reported in 15–75% of patients with hyperthyroidism and usually resolve with treatment. Increased serum alkaline phosphatase is the most common abnormality (including the bone isoenzyme), but there may be elevated aminotransferases and bilirubin. Jaundice attributable purely to hyperthyroidism is uncommon, usually seen during a thyroid storm where canalicular and sometimes hepatocellular cholestasis with associated swelling injury on liver biopsy are described. Other changes are mild and nonspecific. Jaundice in hyperthyroidism can also be precipitated in the presence of heart failure or concurrent liver disease, including associated PBC. In such patients, the role of the hyperthyroidism in causing jaundice may be overlooked.