Systemic disorders in liver diseases: a review

The liver is the "central station" of metabolism: it produces coagulation proteins, regulates carbohydrate and fat metabolism, and detoxifies toxins and hormones. Therefore, chronic liver diseases are rarely limited to the liver itself: the heart and blood vessels, lungs, kidneys, muscles and bones, the nervous system, the immune system, and the hemostatic system are almost always involved. The more severe the liver failure and portal hypertension, the more extensive and dangerous the extrahepatic manifestations. [1]

The classic "portrait" of decompensated cirrhosis includes ascites, encephalopathy, variceal bleeding, infections, hyponatremia, and acute syndromes (hepatorenal, hepatopulmonary, and portopulmonary hypertension). Concurrently, sarcopenia (loss of muscle mass and strength), nutritional deficiency, osteoporosis, and a blood clotting imbalance (a simultaneous tendency toward both thrombosis and bleeding) develop. These systemic disturbances determine quality of life and prognosis no less than the "liver disease" itself. [2]

In recent years, new evidence and even new international classification codes have emerged for these complications. For example, ICD-10 now has separate codes for hepatopulmonary syndrome and hepatic encephalopathy, and ICD-11 has compact clusters of "special liver diseases" with post-coordination. This helps standardize diagnostics, maintain registries, and plan care (including transplantation). [3]

In practice, working with a "systemic liver" involves early screening and monitoring of complications, timely referral to procedures (endoscopy, transjugular portosystemic shunt), modern pharmacotherapy (for example, terlipressin for hepatorenal syndrome), and a strong nutritional and physical therapy program against sarcopenia. The earlier these are initiated, the shorter the hospital stay and the higher the survival rate. [4]

Code according to ICD-10 and ICD-11

ICD-10-CM has separate entries for systemic complications: K76.7 hepatorenal syndrome, K76.81 hepatopulmonary syndrome, K76.82 hepatic encephalopathy, and “other specified liver diseases” (K76.89). For portal hypertension and varicose veins, codes from sections I81-I86 and I85-I86 are used. This level of detail facilitates accounting and routing (for example, indications for transplantation in hepatopulmonary syndrome or portopulmonary hypertension). [5]

In ICD-11, systemic complications are collected in block DB99 "Certain specified liver diseases": DB99.2 hepatorenal syndrome, DB99.3 portopulmonary hypertension, DB99.4 hepatopulmonary syndrome, DB99.5 hepatic encephalopathy, DB99.7-DB99.8 liver failure. The system allows for post-coordination - adding data on the cause, severity, and associated conditions. [6]

Table 1. ICD codes for key systemic complications

Complication	ICD-10-CM	ICD-11
Hepatorenal syndrome	K76.7	DB99.2
Hepatopulmonary syndrome	K76.81	DB99.4
Portopulmonary hypertension	(in ICD-10 it is coded according to pulmonary hypertension/background; often I27.2 + liver disease code)	DB99.3
Hepatic encephalopathy	K76.82	DB99.5
Liver failure (unspecified)	K72.9 (according to section K72*)	DB99.7 / DB99.8

Epidemiology

Chronic liver disease is a major global problem, accounting for approximately 2 million deaths annually (approximately 4% of all deaths), with the majority of these deaths due to complications of cirrhosis and primary liver cancer. The total number of new cases of cirrhosis in 2019 exceeded 2.0 million, and the number of deaths exceeded 1.47 million. [7]

Hepatopulmonary syndrome is detected in 5-30% of patients undergoing evaluation for liver transplantation (in different registries, from 4 to 47%) and significantly increases mortality without transplantation. It is more often detected in decompensated cirrhosis and often determines priority on the waiting list. [8]

Portopulmonary hypertension occurs in approximately 5-10% of liver transplant candidates and accounts for 5-15% of all cases of pulmonary arterial hypertension; if not detected promptly, it worsens the transplant prognosis. Screening with echocardiography is mandatory for all candidates. [9]

Sarcopenia in cirrhosis is one of the most common "systemic" problems: meta-analyses show an average prevalence of 33-44% (higher in men and with Child-Pugh class C) and a consistent association with survival. This explains the strict nutritional recommendations in current guidelines. [10]

Table 2. Prevalence of key complications

State	Prevalence assessment	Sources
Hepatopulmonary syndrome	5-32% of transplant candidates (range in literature 4-47%)	[11]
Portopulmonary hypertension	5-10% of transplant candidates	[12]
Sarcopenia in cirrhosis	33-44% (higher in severe cases)	[13]
Mortality from cirrhosis (global, 2019)	~1.47 million deaths	[14]

Reasons

Systemic disturbances are a direct consequence of three "drivers": portal hypertension, liver failure, and inflammatory-metabolic shifts. Portal hypertension triggers blood shunting, splenomegaly, hyperdynamic circulation, bacterial translocation, and fluid accumulation. Liver failure reduces protein synthesis (albumin, clotting factors) and impairs the detoxification of ammonia and hormones. [15]

Individual syndromes have their own triggers. Hepatorenal syndrome is the final stage of cirrhotic vasodilation with a decrease in effective arterial volume and renal perfusion; endotoxins and inflammation play a significant role. Hepatopulmonary syndrome develops due to pathological dilation of pulmonary vessels and shunts against the background of liver disease. Portopulmonary hypertension, on the other hand, is an increase in pulmonary vascular resistance and arterial remodeling. [16]

Sarcopenia and osteodystrophy are fueled by protein and energy deficiency, hypogonadism, vitamin D deficiency, chronic inflammation, and branched-chain amino acid metabolism disorders. Alcohol and cholestasis further accelerate bone and muscle loss. [17]

Finally, in patients with cirrhosis, a hemostatic "imbalance" develops: both pro- and anticoagulant factors decline, von Willebrand factor levels increase, and sensitivity to thrombomodulin decreases. Therefore, portal vein thrombosis and bleeding are "two sides of the same coin," and simply relying on the international normalized ratio (INR) is no longer effective. [18]

Risk factors

The risk of systemic complications is increased by decompensated cirrhosis (Child-Pugh class BC), frequent decompensations (ascites, bleeding), hyponatremia, infections (including spontaneous bacterial peritonitis), and alcohol abuse. These markers are particularly associated with hepatorenal syndrome and poor outcome without transplantation. [19]

Hepatopulmonary and portopulmonary syndromes are characterized by prolonged portal hypertension, blood shunting, and inflammatory stimuli. Portopulmonary hypertension is more common in women and in autoimmune liver diseases, and its presence increases surgical risk. [20]

Sarcopenia is promoted by inadequate protein-energy nutrition, frequent fasting periods, nocturnal hypoglycemia, hypogonadism, hypotestosteronemia, vitamin D deficiency, and physical inactivity. Alcohol-induced cirrhosis accelerates the development of sarcopenia. [21]

Bone disorders (hepatic osteodystrophy) are more common in cholestatic liver diseases and alcoholism; the risk of fractures without trauma reaches 7-35% in different cohorts, which requires active screening. [22]

Pathogenesis

Portal hypertension causes hyperdynamic circulation: peripheral vasodilation, high cardiac output, and low systemic vascular resistance. This reduces effective arterial volume and activates vasoconstrictor systems (renin-angiotensin, sympathetic), which in the kidneys leads to vasoconstriction and decreased filtration—the "soil" for hepatorenal syndrome. [23]

Two opposing trajectories develop in the lungs. In hepatopulmonary syndrome, there is diffuse capillary dilation and shunts that impair oxygenation (increased hypoxemia in the upright position—orthodeoxia). In portopulmonary hypertension, there is arterial remodeling and increased resistance, consistent with pulmonary arterial hypertension. Both conditions increase mortality and influence transplant strategy. [24]

Hemostasis imbalance is the key to bleeding/thrombosis paradoxes: a decrease in factors II, V, and VII, along with a deficiency of proteins C and S, is compensated for by an increase in von Willebrand factor and a decrease in ADAMTS13; the result is a fragile equilibrium poorly reflected by the international normalized ratio. This requires new approaches to the prevention and correction of bleeding. [25]

Chronic inflammation, insulin resistance, and branched-chain amino acid deficiency lead to sarcopenia; cholestasis and vitamin D deficiency lead to osteodystrophy. These processes are partially reversible and respond best to combined nutritional and exercise programs. [26]

Symptoms

Systemic manifestations form a "decompensation syndrome": fatigue, decreased exercise tolerance, edema, ascites, leg cramps, susceptibility to infections, itching, nocturnal sleep inversion, and cognitive difficulties (hepatic encephalopathy). On examination, spider veins, palmar erythema, muscle atrophy, and weight loss are observed. [27]

Signs of pulmonary complications include dyspnea, worsening while standing (orthodeoxia), suggesting hepatopulmonary syndrome; progressive exercise intolerance, syncope—possibly portopulmonary hypertension. These symptoms are often masked by ascites and anemia, so targeted screening is necessary. [28]

Hepatorenal syndrome is indicated by a sharp decrease in diuresis, an increase in creatinine in the presence of ascites and hyponatremia in the absence of shock, nephrotoxins, and structural kidney damage. Rapid recognition is important, as the prognosis deteriorates sharply without etiotropic intervention and transplantation. [29]

Sarcopenia manifests as weakness, difficulty climbing stairs, falls, and slow recovery after hospitalization. CT/MRI reveals a low muscle mass index at the level of the third lumbar vertebra. Back pain and fragility fractures suggest osteodystrophy. [30]

Classification, forms and stages

It is clinically convenient to divide systemic complications by target organs: renal (hepatorenal syndrome), pulmonary (hepatopulmonary syndrome, portopulmonary hypertension), neurological (encephalopathy), vascular-hemostasis (hemostasis imbalance), musculoskeletal (sarcopenia, osteodystrophy). Several domains are often present in one patient. [31]

Cirrhosis decompensation is classified as compensated (without ascites and bleeding) and decompensated (ascites, bleeding, encephalopathy, jaundice). The presence of hepatopulmonary or portopulmonary syndrome in itself increases the priority of transplantation and requires a separate evaluation pathway. [32]

Hepatopulmonary syndrome is staged according to PaO₂: mild (≥80 mmHg), moderate (60-79), severe (50-59), very severe (≤50). Portopulmonary hypertension is staged according to hemodynamics of right heart catheterization and functional class. [33]

Sarcopenia is defined by loss of muscle mass and strength: the L3 muscle area index on CT and handgrip/chair rise test are validated criteria; the lower the scores, the higher the risk of complications and death. [34]

Table 3. Organ domains of systemic disorders in liver diseases

Domain	Examples of states	Basic screening
Kidneys	Hepatorenal syndrome	Creatinine, sodium, urine analysis, exclusion of nephrotoxins
Lungs/vessels	Hepatopulmonary syndrome, portopulmonary hypertension	Lying/standing pulse oximetry, echocardiography, blood gas analysis
Nervous system	Hepatic encephalopathy	Clinic, psychometry (in minimal form)
Hemostasis	"Rebalance", portal thrombosis	Hemostasis table, viscoelastic tests according to indications
Muscles/bones	Sarcopenia, osteodystrophy	Mass/strength, CT-L3, densitometry, vitamin D

Complications and consequences

Without active management, systemic complications lead to rehospitalizations, infections, bleeding, falls, and fractures, and dramatically increase the risk of death. Hepatopulmonary and portopulmonary syndromes impair survival and may limit the availability of transplantation without prior correction. [35]

Hepatorenal syndrome is one of the most fatal complications of decompensation; without transplantation, the liver-renal axis often progresses to dialysis and multiple organ failure. The approval of terlipressin has changed the standard of care, but early diagnosis and patient selection are critical. [36]

Sarcopenia reduces the tolerance of procedures (including transplantation), increases the frequency of infections, and delays rehabilitation. Osteodystrophy increases the risk of low-energy fractures (7-35% in cohorts), which directly impacts quality of life. [37]

Errors in assessing coagulopathy (relying solely on the international normalized ratio and platelets) can lead to either overcorrection with blood products and thrombosis, or to underestimation of the risk of bleeding during endoscopy/puncture. Modern approaches and selective use of viscoelastic tests are needed. [38]

When to see a doctor

Immediately - if there is increasing shortness of breath (especially worsening while standing), syncope, black stools/"coffee ground" vomit, a sharp drop in urine output, confusion, severe weakness, or fever. This may indicate hepatopulmonary syndrome, variceal bleeding, hepatorenal syndrome, encephalopathy, or infection. [39]

In the coming days - with new ascites/rapid abdominal growth, increasing edema, refractory itching, leg cramps, falls, weight loss or muscle wasting - a review of nutrition, training and therapy is necessary, sometimes - a referral for a transjugular portosystemic shunt. [40]

When preparing for transplantation, it is essential to report any episodes of shortness of breath, decreased oxygen saturation, fainting, and exercise intolerance: this determines the scope of additional examination (echocardiography, blood gas analysis, right heart catheterization). [41]

It is important for patients and families to know that early treatment when symptoms change reduces the risk of severe complications and saves transplantability. [42]

Diagnostics (tests, instrumental diagnostics, step-by-step)

Step 1. Basic "decompensation package." Complete blood count and biochemistry (including bilirubin, albumin, creatinine, sodium), coagulation profile, C-reactive protein; portal flow Doppler ultrasound; diagnostic paracentesis for any new/worsening ascites. The goal is to confirm decompensation and exclude infections and thromboses. [43]

Step 2. Screening for pulmonary syndromes. Pulse oximetry in the supine/standing position (a drop in saturation during verticalization is a clue to hepatopulmonary syndrome), arterial blood gas composition; echocardiography for all transplant candidates to detect portopulmonary hypertension; if suspected, right heart catheterization. [44]

Step 3. Renal assessment. Exclude shock, hypovolemia, nephrotoxins, and structural damage; if hepatorenal syndrome is suspected, administer early albumin testing and vasoconstrictor therapy according to protocol, while simultaneously discussing transplantation/bridge strategy. [45]

Step 4. Muscles and bones. Screening for sarcopenia (mass and strength: handgrip, stool test, CT-L3 if available), densitometry for cholestasis/long-term cirrhosis, assessment of vitamin D and calcium. Concurrent nutritional assessment (required with protein calculation). [46]

Table 4. Mini-algorithms for two “elusive” syndromes

Syndrome	Diagnostic path	Key criterion
Hepatopulmonary	Saturation lying/standing → blood gas composition → contrast echo for intrapulmonary shunts	PaO₂ ↓ and intrapulmonary shunts in liver disease
Portopulmonary hypertension	Echo for all candidates → if suspected, right heart catheterization	Increased pulmonary vascular resistance in the presence of portal hypertension

Differential diagnostics (popular science)

Shortness of breath in a patient with cirrhosis is not always due to "ascites and anemia." Hepatopulmonary syndrome worsens with vertical positioning, portopulmonary hypertension causes exertional dyspnea and right ventricular failure, and pulmonary embolism and chronic obstructive pulmonary disease are excluded by CT angiography/spirometry. [47]

Acute renal dysfunction is not always hepatorenal syndrome: it is important to rule out hypovolemia (diarrhea, diuretics), intrarenal causes (acute tubular necrosis), and obstruction. Clues include urinalysis, renal ultrasound, and albumin response. [48]

Bleeding in cirrhosis is not always due to "low platelets": portal hypertension (varicose veins) is often the cause, and sometimes thrombosis due to "imbalance." Hence the importance of endoscopy and Doppler ultrasound, rather than blindly adjusting the international normalized ratio. [49]

Weakness and falls are not just "asthenia." Sarcopenia is diagnosed objectively (weight and strength) and requires active nutritional and training strategies; depression and iron deficiency are frequent companions and require treatment. [50]

Treatment

1) Basic principles. Management of complications is based on eliminating triggers (alcohol, infections, nephrotoxins), controlling portal hypertension, and maintaining "reserves" (protein, energy, micronutrients, physical activity). Early contact with the transplant center in case of any decompensation is a strategic measure. [51]

2) Ascites and recurrent decompensations. Dietary sodium restriction, spironolactone ± furosemide, regular paracentesis for tense ascites with albumin; if refractory, consider TIPS (transjugular portosystemic shunt) as a bridge to transplantation. [52]

3) Hepatorenal syndrome. Initial therapy: albumin + vasoconstrictors. Since September 2022, terlipressin (Terlivaz) has been approved in the US—the first drug proven to increase the chance of reversibility of HRS-AKI; it is important to avoid it in patients with a high risk of respiratory complications and monitor its effectiveness. Where terlipressin is unavailable, norepinephrine should be administered in the intensive care unit. A parallel waitlist for transplantation is maintained. [53]

4) Hepatic encephalopathy. First-line therapy is lactulose titrated to 2-3 soft stools per day (avoid dehydration). For secondary prophylaxis after a relapse, rifaximine is added; this reduces the risk of new episodes. It is essential to identify and treat any triggers (infection, bleeding, constipation, electrolyte imbalances). [54]

5) Hepatopulmonary syndrome. Symptomatically, oxygen is given for hypoxemia; radical therapy is liver transplantation, which can completely reverse the syndrome. Selection based on the severity of PaO₂ and risks is mandatory; in very severe forms, the risk of perioperative complications increases, but survival data after transplantation are encouraging. [55]

6) Portopulmonary hypertension. Management is based on pulmonary hypertension guidelines: hemodynamic assessment, specific vasodilator therapy (phosphodiesterase-5 inhibitors, endothelin receptor antagonists, prostanoids) as indicated, followed by consideration of transplantation after optimization of pulmonary artery pressure. Regular screening is mandatory for all transplant candidates. [56]

7) Hemostasis "rebalance" and invasive interventions. Routine prophylactic correction of the international normalized ratio/platelet count is not indicated in stable patients; decisions are made based on the clinical presentation and risk of intervention, with an eye toward the use of viscoelastic methods in high-risk cases. Anticoagulation for portal vein thrombosis may be indicated and safe with proper selection. [57]

8) Sarcopenia: nutrition and exercise. Recommended intake is 1.2-1.5 g protein/kg body weight per day (higher in decompensation), adequate energy, minimization of "night hunger" (late protein snacks), and preference for plant and dairy proteins. Resistance training 2-3 times per week and aerobic exercise are added. Branched-chain amino acid supplementation is an option: meta-analyses show benefits for a number of outcomes (including the risk of encephalopathy), although the results for "pure" muscle strength are mixed. [58]

9) Osteodystrophy and fracture prevention. Screening for vitamin D deficiency and densitometry in risk groups (cholestasis, long-term cirrhosis, steroids). The basis is vitamin D and calcium, abstinence from alcohol, physical activity with weights; if indicated, bisphosphonates (with caution in cases of high osteonecrotic vulnerability of the jaw and reflux). The goal is to reduce the risk of fractures, which in patients with chronic liver disease can reach 7-35%. [59]

10) Liver transplantation and "bridges." For hepatopulmonary syndrome, recurrent bleeding, refractory ascites, and progressive hepatorenal syndrome, transplantation remains the only definitive treatment. "Bridges" include TIPS, vasoactive drugs, nutritional and physical therapy programs, and active albumin administration when appropriately indicated. [60]

Table 5. Targeted therapy for key complications

State	First line	Alternatives/additions
Ascites (refractory)	Paracentesis + albumin, diuretics	TIPS, transplant waiting list
Hepatorenal syndrome	Albumin + terlipressin (or norepinephrine in ICU)	Early waiting list, dialysis as a bridge
Encephalopathy	Lactulose, trigger correction	Rifaximin for relapse prevention
Hepatopulmonary syndrome	Oxygen	Liver transplantation
Portopulmonary hypertension	Specific therapy for PAH, optimization	Transplantation after stabilization

Table 6. Nutrition and exercise for cirrhosis (short checklist)

Component	Recommendation
Protein	1.2-1.5 g/kg/day
Energy	Individually, often 30-35 kcal/kg/day
Snacks	Late night snack with protein/carbohydrates
Workout	Strength training 2-3 times a week + aerobic training
Supplements	Branched-chain amino acids according to indications

Prevention

The basics are monitoring the underlying cause (viral hepatitis, alcohol, metabolic dysfunction) and early screening for complications: endoscopy for varicose veins, Doppler ultrasound, testing, vaccinations (hepatitis A/B, pneumococcus, influenza), and nutritional support. This reduces the incidence of decompensation and hospitalization. [61]

For patients with decompensation, a “trigger minimization” program is recommended: no non-steroidal anti-inflammatory drugs and nephrotoxic drugs, caution with sedatives, early treatment of infections, control of constipation and water-electrolyte balance. [62]

For transplant candidates, mandatory screening for portopulmonary hypertension (echo) and hepatopulmonary syndrome (saturation, blood gases), as well as a preparation protocol (vaccinations, physical optimization, nutrition) is required. [63]

Against sarcopenia and osteodystrophy - early training and nutrition (see table), correction of vitamin D, abstinence from alcohol, safe sun exposure and weight training. [64]

Forecast

Globally, the prognosis is determined by the presence and severity of systemic complications. The presence of hepatopulmonary or portopulmonary syndromes without transplantation worsens survival; successful transplantation can completely reverse hypoxemia in hepatopulmonary syndrome and significantly improve the course of portopulmonary hypertension with carefully selected preoperative therapy. [65]

In hepatorenal syndrome, the advent of terlipressin has improved short-term outcomes, but long-term survival still depends on transplantation. It is important to recognize the syndrome early and promptly initiate treatment. [66]

Sarcopenia and nutritional deficiencies are strong independent predictors of death and complications; fortunately, they are modifiable by active nutrition and exercise programs, especially when initiated before major interventions. [67]

At the population level, despite the increase in absolute numbers of cases, standardized mortality rates from cirrhosis are declining - thanks to vaccinations, antiviral therapy, better prevention of complications and the development of transplantation. [68]

Table 7. What improves/worsens the prognosis

Factor	Influence
Early screening and correction of complications	Improves survivability
Presence of HPS/PoPH without transplantation	It makes it worse
Terlipressin for HRS + timely routing	Improves short-term outcomes
Sarcopenia/crowning without intervention	It makes it worse

FAQ

1) Why do I have "poor coagulation tests," but the doctor won't transfuse plasma before the endoscopy?
In cirrhosis, coagulation is "out of balance": simple tests often overestimate the risk of bleeding. The decision to correct it is made individually, taking into account the procedure and modern tests. [69]

2) Is the shortness of breath due to ascites or the lungs?
If it's worse when standing and better when lying down, this is typical of hepatopulmonary syndrome; with portopulmonary hypertension, shortness of breath increases with exertion, and fainting is possible. The examination includes oxygen saturation while lying down/standing, blood gases, and echocardiography. [70]

3) Is it possible to "pump up" muscle with cirrhosis?
Yes. Protein 1.2-1.5 g/kg/day, a late snack, strength training 2-3 times a week and, if indicated, branched-chain amino acids improve muscle mass/function and reduce the risk of decompensation (although the effect on net strength varies between studies). [71]

4) What to do if urine output drops and creatinine levels rise?
Don't delay: rule out dehydration/nephrotoxins, perform an albumin test, and discuss vasoactive therapy. In countries where terlipressin is available, its early administration improves the likelihood of reversibility. At the same time, contact the transplant center. [72]

5) Will TIPS help "forever against ascites"?
TIPS often controls refractory ascites and reduces the frequency of paracentesis. However, the method requires selection (risks of encephalopathy, cardiopulmonary contraindications) and is considered a bridge to transplantation, not a panacea. [73]

Table 8. Mini-screening for systemic complications at each visit

What to ask/measure	For what
Saturation at rest and after a 3-minute walk	Early HPS/PoPH Search
Body weight, handgrip, chair rise test	Sarcopenia
Diuresis/thirst/NSAID medications	HRS risk
Constipation/sleep/confusion	Encephalopathy
Vaccination status	Infection prevention