Bacterial infections are a common cause of morbidity and mortality in patients with cirrhosis, affecting about 30% of such patients either at admission or during their hospitalization, with an attendant risk of mortality that is twice that of individuals without cirrhosis1.
Two major mechanisms may account for the observed immune dysfunction in cirrhosis: 1. Compromise of the immune surveillance function of the liver itself through damage of the reticulo-endothelial system (RES) and reduced synthesis of innate immunity proteins and pattern recognition receptors (PRRs); and 2. Dysfunctions of circulating and intestinal population of immune cells2.
Damage to the RES in cirrhosis leads to portal-system shunting, loss/damage of Kupffer cells (specialized hepatic macrophages) and sinusoidal capillarization, all hindering blood-borne pathogen clearance. Cirrhosis is also associated with a defect in hepatic protein synthesis, including complement components, decreased PRRs and acute phase reactants (eg C-reactive protein), which may in turn lead to the impairment of the innate immunity and bacterial opsonization.
Cirrhosis can also cause reduction in the number and function of neutrophils (eg, decreased phagocytosis and chemotaxis), B, T, and NK lymphocytes, and decreased in bacterial phagocytosis by monocytes. In addition, damage to the gut-associated lymphoid tissue (eg Peyer’s patches and mesenteric lymph nodes) may facilitate bacterial translocation.
- Pieri G, Agarwal B, Burroughs AK. C-reactive protein and bacterial infections in cirrhosis. Ann Gastroenterol 2014;27:113-120. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982625/pdf/AnnGastroenterol-27-113.pdf
- Albillos A, Lario M, Alvarez-Mon M. Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance. J Hepatol 2014;61:1385-1396. http://www.journal-of-hepatology.eu/article/S0168-8278(14)00549-2/pdf
CRP is primarily synthesized by the liver mainly as a response to IL-6 production in inflammatory states1. Lower CRP production may then be expected in cirrhotic patients with significant infections and several studies support this view2.
In a particularly convincing study involving E. coli-infected patients with bacteremia, the median CRP level in cirrhotic patients was about 40% that of non-cirrhotic patients (62 mg/L vs 146 mg/L)3. In another study involving bacteremic patients with or without liver dysfunction, median CRP level was about 60% that of patients with preserved liver function (81 mg/L vs 139 mg/L)4. Some investigators have reported a cut-off CRP value of 9.2 mg/L as a possible screening test for bacterial infections in patients with cirrhosis with a sensitivity and specificity of 88% (AUROC 0.93)5.
Collectively, these data suggest that although CRP response may be diminished in patients with advanced liver disease and acute infection, its synthesis is still maintained.
- Pieri G, Agarwal B, Burroughs AK. C-reactive protein and bacterial infection in cirrhosis. Ann Gastroenterol 2014;27:113-20. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982625/pdf/AnnGastroenterol-27-113.pdf
- Ha YE, Kang C-I, Joo E-J, et al. Usefulness of C-reactive protein for evaluating clinical outcomes in cirrhotic patients with bacteremia. Korean J Intern Med 2011;26:195-200. http://pubmedcentralcanada.ca/pmcc/articles/PMC3110852/pdf/kjim-26-195.pdf
- Park WB1, Lee KD, Lee CS et al. Production of C-reactive protein in Escherichia coli-infected patients with liver dysfunction due to liver cirrhosis. Diagn Microbiol Infect Dis. 2005 Apr;51(4):227-30. https://www.ncbi.nlm.nih.gov/pubmed/15808312
- Mackenzie I, Woodhouse J. C-reactive protein concentrations during bacteraemia: a comparison between patients with and without liver dysfunction. Intensive Care Med 2006;32:1344-51. https://www.ncbi.nlm.nih.gov/pubmed/16799774
- Papp M, Vitalis Z, Altorjay I, et al. Acute phase proteins in the diagnosis and prediction of cirrhosis associated bacterial infection. Liver Int 2011;603-11. https://www.ncbi.nlm.nih.gov/pubmed/22145664
Hepatocellular carcinoma (HCC) is the 3rd most common cause of cancer-related deaths1. Liver transplant removes the HCC tumor and addresses the underlying cirrhosis. Unfortunately, the demand for liver transplants exceeds the supply of available livers, making it necessary to select patients with the best recurrent-free survival following transplantation. .
Mazzaferro2 found that patients who had one lesion <5 cm, no more than 3 lesions each ❤ cm, and no extrahepatic involvement or vascular invasion had significantly higher rates of recurrent-free survival following liver transplant than patients with tumors exceeding this criteria (92% vs 59% at 4 years, respectively, P = .002). This criteria, also known as the Milan criteria, has been substantiated by numerous studies3 and widely adopted. Other more inclusive criteria has also been proposed, including the UCSF criteria4 (one tumor <6.5 cm, no more than 3 tumors, all <4.5 cm and cumulative size <8cm) which have good survival rates, but have not been adopted due to limited supply of available livers.
Interestingly, patients with HCC not initially meeting the Milan criteria but who receive treatment to meet the criteria have similar post-transplantation recurrence-free survival rates as those who meet the criteria without downstaging4,5.
- El–Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007 Jun 30;132(7):2557-76.
- Mazzaferro V, Regalia E, Doci R, et al. L. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996; 334: 693-699.
- Mazzaferro V, Bhoori S, Sposito C, et al. Milan criteria in liver transplantation for hepatocellular carcinoma: an evidence‐based analysis of 15 years of experience. Liver Transplantation 2011;17(S2): S44-S57.
- Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: comparison of the proposed UCSF criteria with the Milan criteria and the Pittsburgh modified TNM criteria. Liver transplantation. 2002 Sep 1;8(9):765-74.
- Ravaioli M, Grazi GL, Piscaglia F, et al. Liver transplantation for hepatocellular carcinoma: results of down-staging in patients initially outside the Milan selection criteria. Am J Transplant. 2008;8:2547–2557.
- Yao FY, Kerlan RK, Hirose R, et al. Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: an intention-to-treat analysis. Hepatology. 2008;48:819–827.
Contributed by Marissa Shoji, Medical Student, Harvard Medical School
Yes! Besides expanding the circulatory plasma volume by raising the oncotic pressure, albumin appears to have a vasoconstricting effects by binding to endotoxins, nitric oxide (NO), bilirubin and fatty acids1,2. Splanchnic vasodilatation, a feature of decompensated cirrhosis (eg ascites, bleeding varices, hepatorenal syndrome, and hepatic encephalopathy), is accentuated by superimposed infections through cytokine-mediated release of endothelial vasodilators3. By binding to potential vasodilators such as bile acids, endotoxins and NO, albumin may also help restore endothelial function and act as a vasoconstrictor.
In a cool study involving patients with SBP randomized to either albumin or hydroxyethyl starch (HS, a synthetic volume expander), the albumin (not HS) group had a significant increase in mean arterial pressure, right atrial pressure, pulmonary artery pressure, systolic volume, left ventricular stroke work, and systemic vascular resistance3.
Albumin may also have an immune-modulating activity in patients with cirrhosis or acute liver decompensation by binding to prostaglandin E-2 (PGE-2), generated as a result of inflammatory reaction in the liver and bacterial translocation4. PGE-2 is a suppressor of macrophage cytokine secretion and bacterial killing. By binding to PGE-2, albumin can reverse this immunosuppression by reducing the availability of serum PGE-2.
- Baraldi O, Valenini C, Donati G, et al. Hepatorenal syndrome: update on diagnosis and treatment 2015;4:511-20.
- Angeli P, Volpin R, Piovan D, et al. Acute effects of the oral administration of midodrine, an α-adrenergic agonist, on renal hemodynamics and renal function in cirrhotic patients with ascites. Hepatology 1998;28:937-43.
- Fernandez J, Monteagudo J, Bargallo X, et al. A randomized unblended pilot study comparing albumin versus hydroxyethyl starch in spontaneous bacterial peritonitis. Hepatology 2005;42:627-634.
- Gleeson, MW, Dickson RC. Albumin gains immune boosting credibility. Clin Transl 2015;6:e86;doi:10.1038/ctg.2015.11.
Spider angiomas (SAs), collections of small blood vessels radiating from a central, dilated arteriole that form near the surface of the skin, are found in 10-15% of healthy adults and young children, as well as in a variety of conditions, including pregnancy, women taking oral contraceptive pills (OCPs), thyrotoxicosis, and chronic liver disease1. Although the exact mechanism of their formation has not been fully elucidated, several hypotheses have been offered.
Some hypothesize that SAs form due to arteriolar vasodilation caused by estrogen excess that occurs as a result of impaired hepatic metabolism in cirrhosis2;this is supported by their association with other high-estrogen states, such as in pregnancy and OCP use. The vasodilatory effects of substance P, a neuropeptide partially inactivated by the liver and elevated in patients with liver disease, may also play a role3. Neovascularization promoted by vascular endothelial growth factor and basic fibroblast growth factor released by damaged hepatocytes has also been implicated4. Alcohol itself may contribute, as SAs are more commonly seen in individuals with alcoholic cirrhosis than in those with non-alcoholic causes of liver disease2.
For unknown reasons, in adults, spider angiomas most commonly occur in areas drained by the superior vena cava, namely the face, arms, neck, and chest.
- Khasnis A, Gokula RM. Spider nevus. J Postgrad Med 2002;48:307.
- Li CP, Lee FY, Hwang SJ, et al., Spider angiomas in patients with liver cirrhosis: role of alcoholism and impaired liver function. Scand J Gastroenterol 1999; 34: 520-3.
- Li CP, Lee FY, Hwang SJ, et al., Role of substance P in the pathogenesis of spider angiomas in patients with nonalcoholic liver cirrhosis. Am J Gastroenterol 1999; 94: 502-7.
- Li CP, Lee FY, Hwang SJ, et al., Spider angiomas in patients with liver cirrhosis: role of vascular endothelial growth factor and basic fibroblast growth factor. World J Gastroenterol 2003; 9: 2832-5.
Contributed by Camille Mathey-Andrews, Medical Student, Harvard Medical School
High serum B12 levels, aka hypercobalaminemia (HC), is not rare among hospitalized patients with 1 study reporting “high” (813-1355 pg/ml) and “very high” (>1355 pg/ml) serum B12 levels in 13 and 7% of patients, respectively1. Common causes include excess B12 intake, solid neoplasms (particularly, hepatocellular carcinoma and metastatic neoplastic liver disease), blood disorders (eg, myelodysplastic syndrome, CML, and acute leukemias, particularly AML3), and other liver diseases, including alcohol-related diseases as well as acute and chronic hepatitis. Other inflammatory states and renal failure have also been reported2.
Paradoxically, even in the presence of HC, a functional B12 deficiency may still exist. This may be related to poor B12 delivery to cells due to its high binding by transport proteins transcobalamin I and III in HC which may in turn cause a decrease in the binding of B12 to transcobalamin II, a key player in B12 transport to tissues2. In this setting, elevated serum methylmalonic acid and homocysteine levels may be helpful.
- Arendt JFB, Nexo E. Cobalamin related parameters and disease patterns in patients with increased serum cobalamin levels. PLoS ONE 2012;9:e45979.
- Andres E, Serraj K, Zhu J. et al. The pathophysiology of elevated vitamin B12 in clinical practice. Q J Med 2013;106:505-515.
The reported prevalence of AI in patients with liver disease varies widely (30-60%)1. However, there is no consensus on how to define AI in such patients, nor is the methodology for its evaluation standardized. A common criticism is the frequent reliance on total, not free, serum cortisol in cirrhosis which may overestimate the prevalence of AI because cortisol is bound to corticosteroid binding globulin and albumin, commonly found at lower concentrations in cirrhosis. However, even when based on measuring free cortisol, AI is found in 12%-29% of clinically stable cirrhotic patients1.
Secondary AI due to hypothalamic-pituitary dysfunction has been reported in Child-Pugh class A, B, and C patients (42%, 69%, and 80%, respectively)2. The mechanism of AI in cirrhosis is unclear, but low serum cholesterol in cirrhosis leading to lack of substrate for steroidogenesis, and increased levels of circulating endotoxin and pro-inflammatory cytokines impairing the hypothalamic-pituitary-adrenal axis have been postulated1.
- Fede G, Spadaro L, Purrello F. Review: adrenal insufficiency in liver disease. J Liver 2014;3:1.
- Zietz, B, Lock, G, Plach, B, et al. Dysfunction of the hypothalamic-pituitary-glandular axes and relation to Child-Pugh classification in male patients with alcoholic and virus-related cirrhosis. Eur J Gastroenterol Hepatology 2003;15:495-501.