Paroxysmal Nocturnal Hemoglobinuria (PNH)

A 38-year-old man presents to his primary care physician with complaints of dark-colored urine over the past few months. He also reports fatigue, generalized weakness, shortness of breath, and intermittent abdominal pain. He has a history of recurrent unexplained anemia requiring blood transfusions and a prior episode of deep venous thrombosis. On examination, he has pallor. Vital signs are stable. Laboratory studies show hemoglobin 8.0 g/dL, MCV 100 fL, reticulocytosis, markedly elevated LDH, elevated indirect bilirubin, and low haptoglobin. Direct antiglobulin test (Coombs test) is negative. High-sensitivity flow cytometry using FLAER on leukocytes and GPI-anchored protein markers demonstrates a GPI-deficient clone with loss of proteins including CD55 and CD59. Diagnosis?

Diagnosis is Paroxysmal Nocturnal Hemoglobinuria (PNH).

1. Definition

Paroxysmal nocturnal hemoglobinuria is a rare acquired clonal hematopoietic stem cell disorder, usually caused by an acquired somatic mutation in the PIGA gene, resulting in deficiency of glycosylphosphatidylinositol (GPI)-anchored proteins. It is clinically characterized by complement-mediated intravascular hemolysis, thrombosis, and variable bone marrow failure.

2. Pathophysiology

1.      An acquired somatic mutation in the PIGA gene on the X chromosome impairs synthesis of the GPI anchor

2.      This causes deficiency of GPI-anchored complement regulatory proteins, particularly CD55 and CD59

3.      Loss of CD55 and CD59 makes erythrocytes abnormally susceptible to complement-mediated intravascular hemolysis

4.      Free plasma hemoglobin scavenges nitric oxide

5.      Nitric oxide depletion contributes to smooth muscle dysfunction, causing:

o    Abdominal pain

o    Dysphagia or esophageal spasm

o    Erectile dysfunction

6.      Complement activation, platelet activation, endothelial dysfunction, and impaired fibrinolysis contribute to thrombosis

3. Clinical Features

3.1 Hemolysis

1.      Hemoglobinuria causing dark-colored urine

2.      Fatigue

3.      Pallor

4.      Dyspnea

5.      Coombs-negative intravascular hemolytic anemia

6.      Hemoglobinuria may occur at any time and is not necessarily nocturnal

3.2 Thrombosis

1.      Venous thrombosis is a major complication

2.      Thrombosis may occur at typical or unusual venous sites

3.      Characteristic sites include:

o    Hepatic veins, causing Budd-Chiari syndrome

o    Portal and mesenteric veins

o    Cerebral venous sinuses

4.      Deep venous thrombosis and pulmonary embolism may also occur

3.3 Bone Marrow Dysfunction

1.      Cytopenias may occur

2.      PNH is strongly associated with aplastic anemia

3.      PNH clones may also occur with other bone marrow failure disorders

3.4 Other Features

1.      Abdominal pain

2.      Dysphagia or esophageal spasm

3.      Erectile dysfunction

4.      Renal impairment

5.      Pulmonary hypertension

4. Laboratory Findings

1.      Anemia

2.      Reticulocytosis

3.      Markedly elevated LDH

4.      Indirect hyperbilirubinemia

5.      Low or undetectable haptoglobin

6.      Usually negative direct antiglobulin test in untreated PNH

7.      Hemoglobinuria

8.      Hemosiderinuria may occur with chronic intravascular hemolysis

9.      Leukopenia or thrombocytopenia may occur with associated bone marrow failure

10.  MCV may be normal or mildly elevated because reticulocytes are larger than mature erythrocytes

5. Diagnosis

1.      High-sensitivity multiparameter flow cytometry is the diagnostic method of choice for detecting a PNH clone

2.      FLAER binds the GPI anchor and is used primarily to identify GPI-deficient neutrophils and monocytes

3.      Recommended leukocyte assessment includes:

o    Neutrophils: FLAER with GPI-linked markers such as CD24 or CD157

o    Monocytes: FLAER with GPI-linked markers such as CD14 or CD157

4.      Erythrocytes are typically assessed using:

o    CD235a as an erythroid lineage marker

o    CD59 to identify partial or complete GPI-anchor deficiency

5.      GPI-anchor deficiency should be demonstrated using at least two GPI-linked structures per leukocyte lineage, preferably including FLAER, and comprehensive PNH testing should assess erythrocytes, neutrophils, and monocytes whenever possible

6.      Neutrophil and monocyte clone sizes generally provide the best estimate of the underlying PNH clone because erythrocyte clone size may be reduced by hemolysis or altered by recent transfusion

7.      FLAER is not routinely used for erythrocyte analysis

8.      Flow-cytometry results should be interpreted with the clinical and laboratory findings, because small PNH clones can occur in bone marrow failure disorders without classical hemolytic PNH

9.      Older tests such as the Ham test and sucrose lysis test are obsolete

6. Complications

1.      Thrombosis, a major cause of morbidity and mortality

2.      Acute and chronic kidney disease

3.      Bone marrow failure

4.      Pulmonary hypertension

5.      Severe or recurrent intravascular hemolysis

6.      Association with aplastic anemia

7.      Rare clonal evolution to myelodysplastic syndrome or acute myeloid leukemia

7. Management

7.1 Supportive Care

1.      Red blood cell transfusion when clinically indicated

2.      Replace folate and iron when deficient or clinically indicated

3.      Treat acute thrombosis with therapeutic anticoagulation unless contraindicated

4.      PNH-associated thrombosis is also an important indication for appropriate complement inhibitor therapy

7.2 Complement Inhibitor Therapy

1.      Complement inhibitor therapy is used for clinically significant PNH, including:

o    Symptomatic or clinically significant intravascular hemolysis

o    Significant anemia or transfusion dependence

o    PNH-associated thrombosis

o    Important PNH-related symptoms such as severe fatigue, abdominal pain, dysphagia, or other hemolysis-related complications

2.      A small asymptomatic PNH clone does not automatically require complement inhibitor therapy

3.      Complement inhibitors control complement-mediated manifestations but do not correct underlying bone marrow failure

4.      Terminal C5 inhibitors

o    Eculizumab

o    Ravulizumab

o    Crovalimab

5.      Proximal complement inhibitors

o    Pegcetacoplan, a C3 inhibitor

o    Iptacopan, a factor B inhibitor

o    Danicopan, a factor D inhibitor used as add-on therapy to eculizumab or ravulizumab in selected patients with clinically significant extravascular hemolysis

6.      Complement inhibition reduces hemolysis and transfusion requirements

7.      Terminal C5 inhibition has also markedly reduced the risk of PNH-associated thrombosis

8.      Choice of therapy depends on disease manifestations, previous treatment, residual anemia, breakthrough hemolysis, comorbidities, availability, and patient preference

9.      Complement inhibitors increase susceptibility to serious infections caused by encapsulated bacteria

10.  Patients receiving complement inhibitors should receive appropriate meningococcal vaccination with both MenACWY and MenB vaccines according to current recommendations

11.  Depending on the specific complement inhibitor, vaccination against other encapsulated organisms, including Streptococcus pneumoniae and Haemophilus influenzae type b, may also be required according to the product label and current immunization guidance

12.  Vaccination does not completely eliminate the risk of serious meningococcal infection, so patients require education and urgent evaluation if symptoms of infection develop

7.3 Curative Therapy

1.      Allogeneic hematopoietic stem cell transplantation is the only potentially curative treatment

2.      Because transplantation carries substantial morbidity and mortality, it is generally reserved for selected patients, particularly those with severe associated bone marrow failure or another compelling indication

8. Key Clinical Insight

Coombs-negative intravascular hemolytic anemia + hemoglobinuria + markedly elevated LDH + low haptoglobin + thrombosis + GPI-anchor deficiency = Paroxysmal Nocturnal Hemoglobinuria

In this patient, recurrent intravascular hemolysis, dark urine, abdominal symptoms, previous venous thrombosis, and demonstration of a GPI-deficient clone by high-sensitivity flow cytometry establish the diagnosis of PNH.

References

1.      Sutherland DR, Illingworth A, Marinov I, et al. ICCS/ESCCA consensus guidelines to detect GPI-deficient cells in paroxysmal nocturnal hemoglobinuria (PNH) and related disorders Part 2: reagent selection and assay optimization for high-sensitivity testing. Cytometry B Clin Cytom. 2018;94(1):23-48. doi:10.1002/cyto.b.21610. PMID: 29236353.

2.      Brodsky RA. How I treat paroxysmal nocturnal hemoglobinuria. Blood. 2021;137(10):1304-1309. doi:10.1182/blood.2019003812. PMID: 33512400.

3.      Padilla Kelley T, King H, Malhotra A, et al. Advancements in complement inhibition for PNH and primary complement-mediated thrombotic microangiopathy. Blood Adv. 2025;9(15):3937-3945. doi:10.1182/bloodadvances.2024015777. PMID: 40354320.

Sjögren Syndrome

A 38-year-old woman presents to her primary care physician with complaints of dry eyes and dry mouth for the past 6 months. She reports burning, itching, and a gritty sensation in both eyes and frequently uses artificial tears. She also has difficulty swallowing dry foods and needs to drink water frequently while eating. Examination reveals non-tender bilateral parotid gland enlargement. She has a history of rheumatoid arthritis diagnosed 2 years ago and is taking methotrexate once weekly with folinic acid. Vital signs are within normal limits. Serology shows positive ANA, rheumatoid factor, anti-SSA (Ro), and anti-SSB (La) antibodies. Schirmer test shows reduced tear production. Minor salivary gland biopsy demonstrates focal lymphocytic sialadenitis. Diagnosis?

Diagnosis is Sjögren disease associated with rheumatoid arthritis, traditionally termed secondary Sjögren syndrome.

1. Definition

Sjögren disease is a chronic systemic autoimmune disease characterized by immune-mediated dysfunction and inflammation of the lacrimal and salivary glands, resulting in dry eyes and dry mouth, with possible systemic manifestations.

2. Nomenclature

1.      Sjögren disease is the preferred clinical term

2.      When Sjögren disease coexists with another systemic autoimmune disease meeting its own classification criteria, the term associated Sjögren disease is preferred over secondary Sjögren syndrome

3.      The distinction between standalone and associated Sjögren disease is mainly useful for describing research populations and clinical context

4.      In this patient, Sjögren disease occurs in association with established rheumatoid arthritis

3. Pathophysiology

1.      Autoimmune activation leads to lymphocytic infiltration and dysfunction of exocrine glands

2.      The characteristic salivary gland lesion is focal lymphocytic sialadenitis

3.      Lacrimal and salivary gland dysfunction causes reduced tear and saliva production

4.      B-cell hyperactivity contributes to production of autoantibodies, particularly anti-SSA (Ro) and anti-SSB (La)

5.      Chronic immune stimulation and B-cell activation contribute to an increased risk of B-cell non-Hodgkin lymphoma

4. Clinical Features

4.1 Glandular Features

1.      Keratoconjunctivitis sicca

o    Dry eyes

o    Burning

o    Grittiness or foreign-body sensation

2.      Xerostomia

o    Dry mouth

o    Difficulty swallowing dry foods

o    Frequent need to drink water while eating

3.      Recurrent or persistent salivary gland enlargement, particularly the parotid glands

4.      Dental caries, periodontal disease, and oral candidiasis may occur

4.2 Other Dryness

1.      Vaginal dryness and dyspareunia

2.      Dry skin

3.      Dryness of the upper respiratory tract

4.3 Extraglandular Manifestations

1.      Fatigue

2.      Arthralgia or inflammatory arthritis

3.      Raynaud phenomenon

4.      Cutaneous vasculitis

5.      Interstitial lung disease

6.      Tubulointerstitial nephritis

7.      Distal renal tubular acidosis

8.      Peripheral neuropathy

9.      Cryoglobulinemia

10.  Hypergammaglobulinemia

5. Diagnosis

5.1 Serology

1.      Anti-SSA (Ro)

o    The only autoantibody included as a weighted item in the 2016 ACR/EULAR classification criteria

o    Carries a weight of 3 points

2.      Anti-SSB (La)

o    May be present, usually with anti-SSA

o    Isolated anti-SSB positivity is not an independent item in the 2016 ACR/EULAR classification criteria

3.      ANA

o    Frequently positive but nonspecific

4.      Rheumatoid factor

o    Frequently positive but nonspecific

5.2 Ocular Testing

1.      Schirmer test ≤5 mm in 5 minutes indicates reduced tear production

2.      Ocular staining score ≥5, or van Bijsterveld score ≥4, provides objective evidence of ocular surface involvement

5.3 Salivary Assessment

1.      Unstimulated whole salivary flow ≤0.1 mL/min is abnormal

2.      Salivary gland ultrasonography is a useful noninvasive adjunct but is not currently one of the five items in the 2016 ACR/EULAR classification criteria

5.4 Histopathology

1.      Minor labial salivary gland biopsy is particularly useful in anti-SSA-negative or diagnostically uncertain patients

2.      Characteristic finding is focal lymphocytic sialadenitis

3.      A focus score ≥1 per 4 mm² is considered positive

4.      Biopsy findings may also provide prognostic information, including information relevant to lymphoma risk

5.5 ACR/EULAR Classification Criteria

The 2016 ACR/EULAR criteria assign:

1.      Anti-SSA positivity = 3 points

2.      Focal lymphocytic sialadenitis with focus score ≥1 per 4 mm² = 3 points

3.      Ocular staining score ≥5 or van Bijsterveld score ≥4 = 1 point

4.      Schirmer test ≤5 mm/5 minutes = 1 point

5.      Unstimulated whole salivary flow ≤0.1 mL/min = 1 point

A total score of ≥4 meets the classification threshold in an appropriate patient.

These are classification criteria, not standalone diagnostic criteria. They are intended for appropriate patients with suspected Sjögren disease after relevant exclusion conditions have been considered. The criteria were formally developed and validated for primary Sjögren syndrome, so Sjögren disease associated with another autoimmune disease remains a clinical diagnosis supported by objective glandular, serologic, and histopathologic findings.

6. Complications

1.      Corneal epithelial damage, ulceration, or visual complications from severe dry eye

2.      Dental caries, periodontal disease, and tooth loss

3.      Interstitial lung disease

4.      Renal tubular acidosis and other renal involvement

5.      Peripheral neuropathy

6.      Cryoglobulinemic vasculitis

7.      Increased risk of B-cell non-Hodgkin lymphoma, particularly marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT)

8.      Features associated with increased lymphoma risk include:

o    Persistent salivary gland enlargement

o    Lymphadenopathy

o    Palpable purpura

o    Cryoglobulinemia

o    Low C4

o    Monoclonal gammopathy

7. Management

7.1 Dry Eyes

1.      Preservative-free artificial tears, particularly when frequent application is required

2.      Lubricating gels or ointments for more severe or nighttime symptoms

3.      Topical cyclosporine may be considered for inflammatory dry eye under ophthalmologic supervision

4.      Short courses of topical corticosteroid eye drops may be used in selected patients under ophthalmologic supervision

5.      Punctal plugs may be considered in carefully selected patients, preferably after ocular surface inflammation has been controlled

6.      Severe refractory disease may require specialist therapies such as autologous serum tears

7.2 Dry Mouth

1.      Frequent water intake

2.      Sugar-free or xylitol-containing gum or lozenges

3.      Saliva substitutes

4.      Regular dental review and meticulous oral hygiene

5.      Appropriate fluoride therapy to reduce dental caries risk

7.3 Secretagogues

1.      Pilocarpine

2.      Cevimeline

3.      Most useful when there is residual salivary gland function and no contraindication to muscarinic agonists

7.4 Systemic Therapy

1.      Systemic immunosuppressive therapy is not routinely indicated for isolated sicca symptoms

2.      Treatment should be directed toward the specific systemic manifestation and any coexisting autoimmune disease

3.      A 6 to 12 month trial of hydroxychloroquine may be considered in selected patients with significant fatigue and systemic symptoms

4.      Glucocorticoids should generally be reserved for specific active systemic manifestations and used at the lowest effective dose for the shortest appropriate duration

5.      Conventional immunosuppressive agents, such as methotrexate, azathioprine, or mycophenolate, are not routinely indicated for uncomplicated Sjögren disease but may be used for selected organ-specific systemic manifestations

6.      Rituximab may be considered in selected patients with severe systemic manifestations, such as significant vasculitis, cryoglobulinemia, or refractory organ involvement

7.      In this patient, methotrexate should be managed primarily according to rheumatoid arthritis disease activity and should not be expected to reliably correct sicca symptoms

8. Key Clinical Insight

Dry eyes + dry mouth + parotid enlargement + anti-SSA positivity + reduced Schirmer test + focal lymphocytic sialadenitis = Sjögren disease

In a patient with established rheumatoid arthritis, this represents Sjögren disease associated with rheumatoid arthritis, traditionally called secondary Sjögren syndrome.

References

1.      Price EJ, Benjamin S, Bombardieri M, et al. British Society for Rheumatology guideline on management of adult and juvenile onset Sjögren disease. Rheumatology (Oxford). 2025;64(2):409-439. doi:10.1093/rheumatology/keae152. PMID: 38621708.

2.      Ramos-Casals M, Baer AN, Brito-Zerón MP, et al. 2023 International Rome consensus for the nomenclature of Sjögren disease. Nat Rev Rheumatol. 2025;21(7):426-437. doi:10.1038/s41584-025-01268-z. PMID: 40494962.

3.      Shiboski CH, Shiboski SC, Seror R, et al. 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren's syndrome: a consensus and data-driven methodology involving three international patient cohorts. Arthritis Rheumatol. 2017;69(1):35-45. doi:10.1002/art.39859. PMID: 27785888.

Carcinoid Syndrome

A 55-year-old woman presents to the clinic with intermittent facial flushing, diarrhea, and wheezing for the past 6 months. She also reports crampy abdominal pain, nausea, and loose stools occurring 3 to 4 times daily, along with unintentional weight loss of 8 kg over 6 months. On examination, a holosystolic murmur is heard at the left lower sternal border. Vital signs show blood pressure 120/80 mm Hg, pulse 102/min, respiratory rate 18/min, oxygen saturation 92% on room air, and temperature 99.9°F. Twenty-four-hour urinary 5-HIAA is elevated. MRI of the abdomen and pelvis shows a small bowel mass with multiple liver metastases. Diagnosis?

Diagnosis is carcinoid syndrome due to a metastatic small bowel neuroendocrine tumor.

1. Definition

Carcinoid syndrome is a hormonal syndrome caused by systemic exposure to serotonin and other vasoactive substances released by neuroendocrine tumors. It is characterized primarily by flushing and secretory diarrhea, with possible bronchospasm and carcinoid heart disease.

In gastrointestinal neuroendocrine tumors, carcinoid syndrome usually develops after liver metastases allow tumor-derived mediators to reach the systemic circulation without complete hepatic metabolism.

2. Etiology

1.      Small intestinal neuroendocrine tumors, particularly ileal or other midgut tumors, are the most common cause

o    Carcinoid syndrome usually occurs when liver metastases are present

2.      Bronchopulmonary neuroendocrine tumors

o    May cause carcinoid syndrome without liver metastases because secreted products enter the systemic circulation directly

3.      Ovarian neuroendocrine tumors

o    May also cause carcinoid syndrome without liver metastases

4.      Less commonly:

o    Pancreatic neuroendocrine tumors

o    Other foregut or unknown-primary neuroendocrine tumors

3. Pathophysiology

1.      Neuroendocrine tumors may secrete:

o    Serotonin

o    Tachykinins

o    Histamine

o    Prostaglandins

o    Other vasoactive peptides and amines

2.      Secretory products from gastrointestinal tumors normally enter the portal circulation and are metabolized by the liver

3.      Liver metastases allow large amounts of vasoactive substances to reach the systemic circulation

4.      Serotonin contributes particularly to:

o    Increased intestinal secretion and motility causing diarrhea

o    Fibrotic changes contributing to carcinoid heart disease

5.      Multiple vasoactive mediators contribute to:

o    Flushing

o    Bronchospasm

6.      Serotonin is metabolized to 5-hydroxyindoleacetic acid (5-HIAA), which can be measured in urine or plasma

7.      Chronic diversion of tryptophan toward serotonin synthesis may reduce niacin synthesis and contribute to niacin deficiency or pellagra

4. Clinical Features

4.1 Classic Features

1.      Episodic flushing

o    Usually affects the face, neck, and upper chest

o    May be triggered by alcohol, stress, exercise, or certain foods

2.      Secretory watery diarrhea

3.      Crampy abdominal pain

4.      Bronchospasm or wheezing

5.      Tachycardia or blood pressure fluctuations may occur during episodes

4.2 Carcinoid Heart Disease

1.      Chronic exposure to circulating vasoactive substances causes fibrous plaque deposition on right-sided cardiac valves and endocardium

2.      Tricuspid regurgitation is common

o    May produce a holosystolic murmur at the left lower sternal border

3.      Pulmonary valve stenosis and/or regurgitation may occur

4.      Advanced disease may cause right-sided heart failure

5.      The left side of the heart is usually relatively spared because vasoactive substances are metabolized in the lungs

6.      Left-sided involvement may occur with:

o    Patent foramen ovale or another right-to-left shunt

o    Very high circulating mediator levels

o    Bronchopulmonary neuroendocrine tumors

4.3 Other Features

1.      Weight loss

2.      Malnutrition

3.      Fatigue

4.      Niacin deficiency or pellagra

o    Dermatitis

o    Diarrhea

o    Neurocognitive changes

5.      Mesenteric fibrosis associated with small intestinal neuroendocrine tumors

o    May cause bowel obstruction, ischemia, or abdominal pain

5. Diagnosis

5.1 Biochemical Testing

1.      Twenty-four-hour urinary 5-HIAA is a standard biochemical test for suspected carcinoid syndrome

2.      Because of biological and collection variability, two 24-hour urine collections are preferred

3.      Patients should follow laboratory instructions regarding foods and medications that may interfere with 5-HIAA measurement

o    Serotonin-rich foods and certain medications can produce misleading results

4.      Plasma or serum 5-HIAA is an alternative where validated and available

5.      Chromogranin A

o    May reflect neuroendocrine tumor burden

o    Is nonspecific

o    Does not reliably distinguish patients with from those without carcinoid syndrome

5.2 Imaging

1.      Multiphasic contrast-enhanced CT or MRI is used for localization, staging, and assessment of liver metastases

2.      Somatostatin receptor PET/CT, typically using a radiolabeled somatostatin analogue such as 68Ga-DOTATATE, is preferred for:

o    Whole-body staging

o    Detection of somatostatin receptor-positive disease

o    Determining suitability for peptide receptor radionuclide therapy

3.      Older somatostatin receptor scintigraphy has lower sensitivity and is generally used only when SSTR PET is unavailable

5.3 Histology and Tumor Grading

1.      Tissue diagnosis confirms a neuroendocrine tumor

2.      Neuroendocrine differentiation is supported by markers such as:

o    Synaptophysin

o    Chromogranin

3.      Tumor grade is determined using:

o    Mitotic rate

o    Ki-67 proliferation index

5.4 Cardiac Evaluation

1.      NT-proBNP should be assessed in patients with carcinoid syndrome when carcinoid heart disease is suspected or screening is appropriate

2.      Transthoracic echocardiography is the key imaging test for carcinoid heart disease

3.      Echocardiography evaluates:

o    Tricuspid valve thickening and reduced mobility

o    Tricuspid regurgitation

o    Pulmonary valve involvement

o    Right ventricular size and function

4.      ENETS uses NT-proBNP >260 pg/mL as a threshold prompting echocardiographic assessment

5.      Clinical suspicion or an abnormal cardiac examination warrants echocardiography regardless of NT-proBNP

6.      In this patient, the holosystolic murmur warrants transthoracic echocardiography even without an NT-proBNP result

6. Management

6.1 First-Line Symptom Control

1.      Before attributing all diarrhea to carcinoid syndrome, evaluate for other potential causes, including:

o    Pancreatic exocrine insufficiency

o    Bile acid diarrhea

o    Short bowel syndrome

o    Intestinal ischemia

o    Infection or other gastrointestinal disorders when clinically appropriate

2.      Long-acting somatostatin analogues are first-line therapy for confirmed carcinoid syndrome

o    Octreotide LAR

o    Lanreotide

3.      Somatostatin analogues reduce:

o    Diarrhea

o    Flushing

o    Other hormone-mediated symptoms

4.      They also have antiproliferative activity in well-differentiated neuroendocrine tumors

6.2 Supportive Treatment

1.      Avoid identifiable flushing triggers, such as alcohol and certain foods

2.      Correct dehydration and electrolyte abnormalities

3.      Antidiarrheal therapy, such as loperamide, may be used as adjunctive treatment

4.      Assess nutritional status and replace deficiencies, including niacin, when present

6.3 Persistent or Refractory Carcinoid Syndrome

1.      Confirm adherence and optimize the dose or dosing interval of the somatostatin analogue

2.      Reassess for alternative or contributing causes of diarrhea

3.      Telotristat ethyl

o    Inhibits tryptophan hydroxylase and reduces serotonin production

o    Used for carcinoid syndrome diarrhea inadequately controlled by somatostatin analogue therapy

4.      Additional tumor-directed therapy may improve refractory hormonal symptoms

6.4 Antitumor Therapy for Metastatic Disease

1.      Peptide receptor radionuclide therapy with 177Lu-DOTATATE

o    Recommended after progression on somatostatin analogue therapy in appropriate patients with somatostatin receptor-positive, well-differentiated metastatic gastrointestinal neuroendocrine tumors

2.      Everolimus

o    May be considered as an alternative systemic option for selected patients with progressive advanced neuroendocrine tumors, particularly when PRRT is unsuitable or the tumor is somatostatin receptor-negative

3.      Treatment selection depends on:

o    Tumor grade

o    Somatostatin receptor expression

o    Tumor burden

o    Rate of progression

o    Distribution of metastatic disease

o    Previous treatment

6.5 Surgery and Liver-Directed Therapy

1.      Surgical resection is preferred for localized resectable small intestinal neuroendocrine tumors

2.      In metastatic disease, resection of the primary tumor or cytoreductive surgery may be considered in carefully selected patients

3.      For liver-dominant metastatic disease, selected patients may benefit from:

o    Transarterial embolization

o    Transarterial chemoembolization

o    Radioembolization

o    Thermal ablation

o    Surgical cytoreduction

4.      Management should be individualized by a multidisciplinary neuroendocrine tumor team

6.6 Carcinoid Heart Disease

1.      Optimize control of serotonin and other tumor-secreted mediators

2.      Monitor with NT-proBNP and echocardiography

3.      Treat right-sided heart failure when present

4.      Valve replacement surgery should be considered in appropriately selected patients with severe symptomatic carcinoid valvular disease

6.7 Carcinoid Crisis

1.      Carcinoid crisis is a potentially life-threatening episode characterized by severe hemodynamic instability, flushing, bronchospasm, and other manifestations of acute mediator release

2.      It may occur during:

o    Surgery

o    Anesthesia

o    Tumor manipulation

o    Other invasive procedures

3.      Evidence that prophylactic octreotide completely prevents carcinoid crisis is limited

4.      Peri-procedural somatostatin analogue prophylaxis may be considered, particularly in patients with functional neuroendocrine tumors undergoing surgery or invasive procedures

5.      The anesthesia and procedural teams should be prepared to recognize and immediately treat hemodynamic instability

6.      Management may require:

o    Appropriate intravenous fluids

o    Vasoactive medications

o    Intravenous octreotide as an adjunct

o    Treatment of bronchospasm and other complications as clinically indicated

7. Key Clinical Insight

Episodic flushing + secretory diarrhea + wheezing + elevated 5-HIAA + small bowel neuroendocrine tumor + liver metastases = carcinoid syndrome

The holosystolic murmur at the left lower sternal border strongly suggests tricuspid regurgitation from carcinoid heart disease, so this patient requires cardiac assessment with transthoracic echocardiography, with NT-proBNP used as an additional biomarker.

References

1.      Grozinsky-Glasberg S, Davar J, Hofland J, et al. European Neuroendocrine Tumor Society (ENETS) 2022 Guidance Paper for Carcinoid Syndrome and Carcinoid Heart Disease. J Neuroendocrinol. 2022;34(7):e13146. doi:10.1111/jne.13146. PMID: 35613326.

2.      Perez K, Del Rivero J, Kennedy EB, et al. Symptom Management for Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors: ASCO Guideline. JCO Oncol Pract. 2026;22(1):19-35. doi:10.1200/OP-25-00133. PMID: 40344544.

3.      Del Rivero J, Perez K, Kennedy EB, et al. Systemic Therapy for Tumor Control in Metastatic Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors: ASCO Guideline. J Clin Oncol. 2023;41(32):5049-5067. doi:10.1200/JCO.23.01529. PMID: 37774329.