IFALD was recognized shortly after total parenteral nutrition (TPN) was widely used in the late 1960s.² IFALD is the most common complication of neonates and infants with intestinal failure receiving TPN. The disease manifestations differ in infants versus older children and adults, but biliary sludging and cholecystitis (acalculous and calculus) frequently occur in both.

Neonates who receive TPN usually present with early abnormal liver enzyme tests with no clinical symptoms, but jaundice can develop about 2 weeks after starting TPN. Hepatic dysfunction, hepatic
fibrosis, and splenomegaly gradually progress with the duration of TPN treatment. In infants receiving TPN, the reported incidences of IFALD varies widely from 15% to 85%.³, ⁴, ⁵ The incidence correlates inversely with the gestational age and birth weight and is also related to the underlying disease and duration of treatment. The incidence of cholestasis is 50% in infants with birth weight <1,000 g but falls to 7% if birth weight is >1,500 g.⁶ The highest incidence of IFALD occurs in infants <34 weeks of gestation and <2,000 g body weight.⁷ A prolonged length of TPN increases the overall incidence of liver injury, with cholestasis occurring in 85% of infants who are on TPN >100 days.

IFALD can also develop in older children and adults following TPN, but its incidence is much lower. The clinical presentations are also different from those seen in infants and usually are less severe. After 9 to 12 days of TPN therapy, mildly elevated liver transaminase and alkaline phosphatase levels are observed in 54% to 68% of adult patients, and serum bilirubin levels are elevated in 21% of patients.⁸ Abnormal liver enzyme elevations in adults are usually self-limited. Patients who develop infections while on TPN are at greater risk of developing steatosis and intrahepatic cholestasis. Patients on long term TPN therapy may present with persistent elevations in liver tests and steatohepatitis.⁹

The pathogenesis of IFALD remains poorly understood and is believed to be multifactorial. Known associations include prematurity, low birth weight, duration of TPN, short bowel syndrome, and the frequency of infection. A lack of enteral feeding results in gut mucosal atrophy, and this in turn leads to a disruption of enterohepatic circulation, which is also considered to play an important mechanistic role.¹⁰

Laboratory findings are not specific for IFALD. Elevated conjugated bilirubin levels are usually the earliest sign but may not be significantly elevated in adults with early-phase disease. IFALD is often associated with elevated liver transaminases, alkaline phosphatase levels, and γ-glutamyl transpeptidase (GGT) levels. Total bilirubin levels persistently >5.8 mg/dL for at least 2 to 4 weeks are a marker of severe IFALD.

Elevated liver transaminase levels are commonly observed within the first 2 to 3 weeks of TPN therapy. Typically, this is a transient increase and self-limited in adult patients. However, liver transaminase levels are not sensitive or specific indicators of hepatic dysfunction. In a study of long-term TPN patients, a significant correlation between TPN duration and the serum alkaline phosphatase was observed, although TPN duration and aspartate transaminase (AST) and alanine transaminase (ALT) levels were not correlated.¹¹ A fall in albumin or prolonged coagulation is a late sign of hepatic dysfunction, whereas thrombocytopenia suggests splenomegaly secondary to portal hypertension from advanced hepatic fibrosis or cirrhosis.

Ultrasound of the liver may demonstrate hepatomegaly, a contracted gallbladder, biliary sludge, or gallstones. Splenomegaly may be seen in cases with portal hypertension from cirrhosis.

Explanted livers of end-stage IFALD typically appear shrunken and cirrhotic, with regenerative nodules of various sizes and greenish discoloration because of chronic cholestasis (Fig. 19.1).

There are no specific histological features in IFALD. The liver shows a wide range of morphological changes, with some differences in infants versus older children and adults.¹² The severity of liver injury is related to the length of TPN therapy. Patients with >6 weeks of TPN are more likely to have significant cholestasis and fibrosis.

Cholestasis is the most common finding in both infants and adults. Perivenular hepatocanalicular cholestasis can occur a few days to a few weeks after starting TPN. With disease progression, features of chronic cholestasis can be observed, such as hepatocyte feathery degeneration, cholestatic rosettes, and bile infarcts (Fig. 19.2). Bile plugs can be present in the interlobular bile ducts. Inflammation in the portal tracts and the lobular parenchyma is usually mild and nonspecific. Hepatocellular injury is more severe in infants and can show extensive ballooning and feathery degeneration. Steatosis is more commonly
found in older children and adults, typically seen as mild periportal macrovesicular steatosis (Fig. 19.3). Steatohepatitis can develop after long-term TPN and progress to cirrhosis in a small number of patients.¹³ Ductopenia is frequently seen but is not accompanied by a bile ductular reaction. This ductopenic pattern of injury may have a different mechanism from that of bile sludge or bile duct obstruction, which can also lead to biliary obstructive changes and eventually to biliary cirrhosis with ductopenia (Fig. 19.4).³,¹²

Hepatic fibrosis occurs in essentially all cases of IFALD and is related to the length of treatment. Liver function tests and bilirubin level are not correlated with the degree of fibrosis. Fibrosis is common even after the cholestasis has resolved. Serial liver biopsy may be necessary for staging purposes in cases of long-term IFALD. Portal fibrosis often occurs early in the course of IFALD and may progress rapidly. Progression to cirrhosis is more likely in infants. One study showed that 34% of infants developed cirrhosis, whereas none of 36 patients older than 1 year had cirrhosis.¹² Perivenular fibrosis is also observed in early-stage disease, which is a distinctive feature of IFALD that separates it from other causes of biliary cirrhosis (Fig. 19.5).¹²

Immunohistochemical and special stains are mainly used for evaluating hepatic fibrosis (i.e., trichrome stain) and to exclude entities in the differential diagnosis, such as infection or inherited liver diseases.

Electron microscopy is mainly used as needed to exclude metabolic liver diseases. If there is a specific clinical suspicion or histologic features suggestive of metabolic diseases, a portion of liver biopsy tissue should be saved in glutaraldehyde for electron microscopy.

Molecular genetic testing is mainly used to exclude genetic/metabolic liver diseases if there is specific clinical suspicion or histological features suggestive of those diseases.

Liver involvement in type 2 diabetes covers a wide spectrum of liver diseases, ranging from mildly abnormal liver enzymes to cryptogenic cirrhosis. The most common chronic liver disease associated with diabetes is nonalcoholic fatty liver disease. The prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes is estimated at 34% to 74%.²⁹, ³⁰, ³¹ The details of nonalcoholic fatty liver disease are further discussed in Chapter 16.

Recently, an additional pattern of liver injury was described in long-standing diabetic patients, termed “diabetic hepatosclerosis.”³² This injury pattern is characterized by dense sinusoidal fibrosis, even though the livers are non-cirrhotic in the traditional sense (Fig. 19.8). Alkaline phosphatase elevations are common. Hepatosclerosis can be an independent finding that is not accompanied by nonalcoholic fatty liver disease or GH. Most cases of diabetic hepatosclerosis have evidence of microvascular complications that leads to damage in multiple organs, suggesting that hepatosclerosis is result of microangiopathic disease of the liver. An autopsy study has found a prevalence of 12% in diabetic patients.³³ Indeed, diabetic
microangiopathy in the liver has been associated with hepatosclerosis in a recent study.³⁴

Hepatic dysfunction is often observed in hyperthyroidism, which can range from mild abnormal liver function tests to severe cholestasis and acute liver failure.³⁵, ³⁶, ³⁷ Elevated alkaline phosphatase levels are common and transaminases can also elevate, but they usually normalize when patients become euthyroid. The liver pathology in hyperthyroidism is mild and nonspecific but can include mild steatosis, mild to moderate cholestasis, mild lobular inflammatory inflammation with some eosinophils, and Kupffer cell hyperplasia. In patients who died of thyrotoxicosis, severe liver injury can occur, such as fatty liver, necrosis, venous congestion, and cirrhosis.³⁸ Autoimmune liver diseases, such as primary biliary cirrhosis or autoimmune hepatitis, can also be found in patients with thyroid disease, for example, co-occurring in about 10% of patients with Grave disease.³⁹

Hypothyroid disease can be associated with mild elevations in liver enzymes, which normalize after hormone replacement therapy. The liver biopsy findings are usually normal or show minimal changes.⁴⁰ Hypothyroidism in infants and children may lead to cholestatic liver disease, leading to liver biopsy to rule out other pediatric cholestatic liver diseases. Hypothyroidism is also associated with nonalcoholic fatty liver disease.⁴¹

Hypopituitary disease can be a part of inherited syndromes or secondary to parenchymal loss, for example, following pituitary surgery. In infants, congenital hypopituitarism can manifest as cholestasis and/or neonatal giant cell hepatitis (Fig. 19.9).⁴² There is growing evidence that adult hypopituitary patients can develop a similar phenotype as that of the metabolic syndrome, with central obesity, diabetes, and nonalcoholic fatty liver disease.⁴³ A study has shown that growth hormone replacement therapy in patients with hypopituitary disease can significantly improve the liver function tests and the histological changes of nonalcoholic fatty liver disease.⁴⁴

Hepatobiliary involvement is common in inflammatory bowel disease. Abnormal liver function tests are present in up to 30% of patients with inflammatory bowel disease but do not appear to correlate with disease activity.⁴⁵ Primary sclerosing cholangitis is one of the more common hepatobiliary complications of inflammatory bowel disease, particularly in patients with ulcerative colitis. The association of primary sclerosing cholangitis with inflammatory bowel disease and its manifestation are discussed in more detail in Chapter 13. Most of the medications used in the treatment of inflammatory bowel disease have been associated with a variety of liver injuries, including sulfasalazine, thiopurines, methotrexate, and biological agents. However, the overall incidence of serious complications is low. The general topic of medication-associated liver injury is also discussed in more detail in Chapter 15. The hepatobiliary complications also somewhat differ in ulcerative colitis versus Crohn’s disease (Table 19.1).

In general, the liver can show a range of findings in individuals with inflammatory bowel disease, including minimal to mild nonspecific reactive hepatitis. In these cases, the inflammation may be a result of inflammatory changes in the intestine with increased mucosal permeability, leading to increased antigens in the portal circulation and secondary mild liver inflammation. Steatosis is also a common finding in the livers of inflammatory bowel disease patients, with a prevalence of up to 35%.⁴⁶ The liver shows macrovesicular steatosis, and the extent of fatty liver changes can correlate with the severity of the colitis, especially in ulcerative colitis.⁴⁷ Granulomas with mild inflammatory changes are rare and are predominantly seen in Crohn’s disease (Fig. 19.10). Approximately 3% of patients with granulomatous hepatitis have Crohn’s disease, but it also has been suggested that granulomatous
hepatitis in some cases can be secondary to treatment with sulfasalazine.⁴⁸ If the patient is under active immunomodulatory therapy, the biopsy should be carefully examined for cytomegalovirus (CMV) and other opportunistic infections. Finally, approximately 2% to 5% of inflammatory bowel disease patients with hepatobiliary involvement will develop cirrhosis, primarily because of primary sclerosing cholangitis.⁴⁹

Celiac disease is an autoimmune disorder seen in genetically predisposed people that is induced by a reaction to dietary gluten. Although primarily affecting the small bowel, celiac disease is a multisystem illness that can potentially involve other organs, including the hepatobiliary system. Approximately 30% to 40% of individuals with celiac disease will at some point have elevated transaminases or alkaline phosphatase levels.⁵⁰,⁵¹ In addition, studies have shown that up to 10% of unexplained elevations of liver enzymes will eventually prove to result from celiac disease.⁵²

Transaminases are typically mildly elevated but can occasionally be seen in the several hundreds.⁵³ Mild elevations of antinuclear antibody and anti-smooth muscle antibody can be observed in about 10% of celiac disease patients. Liver enzymes will normalize following gluten-free diet in most cases, although the normalization often takes several months and may take up to a year.

If gluten restriction does not lead to normalized liver tests, then the possibility of other autoimmune liver disorders needs to be ruled out, such as autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis, because they share common genetic factors and immunopathogenesis. Overall, approximately 3% to 7% of individuals with autoimmune hepatitis or primary biliary cirrhosis are found to have celiac disease, although the association was as high as 63% in one study.⁵⁴, ⁵⁵, ⁵⁶ An association with primary sclerosing cholangitis is less clearly established. The histological findings of the associated liver autoimmune disorders are the same as those in patients without celiac disease.

The histological changes in celiac disease are typically very mild and consist mostly of nonspecific portal and lobular chronic inflammation, Kupffer cell hyperplasia, focal ductular proliferation, and often some mild fatty change. This pattern has been referred as celiac hepatitis (Fig. 19.11). Steatosis is often associated with celiac disease, but it is unclear if the fatty change results from coexisting metabolic syndrome or is directly related to the celiac disease. A recent large epidemiological study has shown that individuals with celiac disease have nearly a threefold increased risk of nonalcoholic fatty liver disease compared with the general population.⁵⁷ Portal venopathy and nodular regenerative hyperplasia have also been described in patients with celiac disease.⁵⁸,⁵⁹ In general, the mild inflammatory changes of celiac disease are not associated with fibrosis. Advanced fibrosis or cirrhosis can be seen but, in most cases, appears to be related to coexisting autoimmune liver disease or steatohepatitis.

Rheumatoid arthritis is a systemic autoimmune disorder characterized by symmetric polyarticular joint involvement. Abnormal liver enzymes have been reported in up to 80% of patients with rheumatoid arthritis. Elevated alkaline phosphatase and GGT levels are the predominant biochemical abnormality.⁶⁰,⁶¹ Although rheumatoid arthritis involves bone damage, it has been shown that the predominant source of alkaline phosphatase is the liver. The increase in the liver isoenzyme levels of alkaline phosphatase has been shown to correlate with the clinical activity of rheumatoid arthritis.⁶²,⁶³

The liver histology is usually normal or shows minor alterations, such as variations in nuclear size, congestion, or mild steatosis. Some cases may present with mild nonspecific reactive hepatitis.⁶⁴,⁶⁵ Nodular regenerative hyperplasia has also been reported in a small number of patients with rheumatoid arthritis. Nodular regenerative hyperplasia is more commonly seen in the Felty syndrome, in which rheumatoid arthritis patients also have splenomegaly and neutropenia. It has been reported that nearly 50% of patients with Felty syndrome have nodular regenerative hyperplasia and portal hypertension.⁶⁶ Nodular regenerative hyperplasia in rheumatoid arthritis and Felty syndrome is believed to be associated with rheumatoid vasculitis.⁶⁷ Lipogranulomas have been found in 56% of liver biopsies in rheumatoid arthritis patients, which is thought to be related to treatment, because these granulomas contain gold particles.⁶⁸ Rheumatoid nodules, the pathognomonic feature of rheumatoid arthritis in skin and other organ sites, are rarely reported in the liver.⁶⁹ Rheumatoid nodules are typically large and show a central area of necrosis/fibrosis surrounded by a middle layer of histiocyte-rich inflammation that can show palisading and often has multinucleated giant cells. An outer layer shows chronic inflammation with lymphocytes and plasma cells as well as areas that look like granulation tissue.

Methotrexate is one of the most commonly used drugs in the treatment of rheumatoid arthritis. Liver biopsy is recommended if patients have other significant risk factors for liver disease (alcohol use, chronic viral hepatitis, diabetes, or obesity) or 6 of 12 liver transaminases or serum albumin tests are abnormal in any year. Methotrexate-induced liver histologic changes include steatosis, steatohepatitis, focal necrosis, anisonucleosis, fibrosis, and cirrhosis (Fig. 19.12). If advanced fibrosis or cirrhosis is present on the liver biopsy, then halting methotrexate is typically recommended. Methotrexate also has synergistic effect with other risk factors of steatohepatitis, such as alcohol consumption, and can further aggravate steatohepatitis.

Systemic lupus erythematosus is a systemic autoimmune disease in which the liver can also be affected. Overall, 25% to 50% of systemic lupus erythematosus patients have abnormal liver enzymes.⁷⁰ The histological changes of the liver in systemic lupus erythematosus are extremely variable and can range from normal or minimal changes to cirrhosis. Liver involvement in systemic lupus erythematosus has been classified into three major patterns: (1) lupus hepatitis or systemic lupus erythematosus-associated hepatitis; (2) co-occurrence with other autoimmune liver diseases, such as autoimmune hepatitis and primary biliary cirrhosis; and (3) liver injury due to non-autoimmune etiologies, for example, drug-induced liver damage, viral hepatitis, or thrombotic liver disease, among others.⁷¹

Lupus hepatitis refers to a mild, subclinical liver injury directly associated with systemic lupus erythematosus. Although it is still controversial whether
the hepatic dysfunction is attributed to lupus itself, recent studies have shown that autoantibodies to ribosomal P proteins (anti-ribosomal P), a highly specific marker for systemic lupus erythematosus, are associated with hepatic enzyme abnormalities in patients with systemic lupus erythematosus.⁷² The prevalence of lupus hepatitis is about 10%.⁷³ However, lupus hepatitis is essentially a diagnosis of exclusion. On biopsy, lupus hepatitis shows a very mild nonspecific reactive hepatitis. The inflammation is mainly in the lobules, with lymphocytic inflammation and occasional acidophil bodies. Portal inflammation is absent or very mild. Lupus hepatitis is not associated with either severe or progressive liver injury (Fig. 19.13).